Nitromethyl ketones, process for preparing them and compositions containing them

ABSTRACT

The present invention relates to the compounds of formula: ##STR1## in which R 1 , R 2 , R 3 , E, A, X, Z, p and n are as defined herein. These compounds are aldose reductase inhibitors.

The present invention relates to new nitromethyl ketones, to theirpreparation and to their use as medicaments, especially in the treatmentor prevention of the complications of diabetes.

Diabetes is characterized by a high concentration of glucose in theblood. This glucose is normally metabolized by the enzyme hexokinaseduring the first stage of glycolysis, leading to the degradation intopyruvate. When the glucose concentration is too high, hexokinase becomessaturated and a second pathway for glucose metabolism comes into play.It is the polyol pathway which involves two enzymes successively: aldosereductase which converts glucose to sorbitol and sorbitol dehydrogenasewhich converts sorbitol to fructose. In the event of diabetes, theexcess glucose accelerates the formation of sorbitol which tends toaccumulate. This results in serious metabolic disturbances, such as forexample an increase in osmotic pressure which can lead to tissuedegeneration. Aldose reductase inhibitors are therefore useful fortreating or preventing certain complications induced by diabetes.

Numerous products are described in the literature, such as aldosereductase inhibitors which are active in vitro and in vivo.

They are mainly derivatives of hydantoins, of succinimides and of aceticacids and more recently derivatives of sulfonylnitromethanes.

SUMMARY OF THE INVENTION

The present invention relates to nitromethyl ketone derivatives andtheir addition salts with physiologically acceptable bases,corresponding to the general formula (I): ##STR2## in which A representsC₆ -C₁₀ aryl or an optionally aromatic three- to ten-memberedheterocycle in which one to four ring atoms are identical or differentheteroatoms chosen from O, S and N;

X represents halogen, cyano, C₁ -C₇ alkyl, trifluoromethyl, C₂ -C₇alkoxy or trifluoromethoxy;

R₁ and R₂, which are identical or different, represent a hydrogen atom,a C₁ -C₇ alkyl group, a C₃ -C₁₂ cycloalkyl group, a trifluoromethylgroup, a C₁ -C₇ alkoxy group or R₁ or R₂ together form an alkylene chainof the --(CH₂)_(r) -- type, where r is chosen from 2, 3 and 4;

p is chosen from 0, 1, 2, 3, 4 and 5;

Z represents a bond, the divalent radical --CO--NH-- in which thecarbonyl function is linked to R₃, the divalent radical --SO₂ --NH-- inwhich the sulfonyl function is linked to R₃, a C₂ -C₇ alkenyleneradical, a sulfur atom, the sulfinyl group or a sulfonyl group;

R₃ represents a hydrogen atom; a halogen atom; a tri-(C₁ -C₇-alkyl)silyl group; a C₁ -C₇ alkyl group optionally substituted with oneor more identical or different Y radicals; a C₆ -C₁₀ aryl groupoptionally substituted with one or more identical or different Yradicals; a C₆ -C₁₀ aryloxy group optionally substituted with one ormore identical or different Y radicals; a C₃ -C₁₂ cycloalkyl groupoptionally substituted with one or more identical or different Yradicals; an optionally aromatic three- to ten-membered heterocycle inwhich one to four ring atoms are identical or different heteroatomschosen from O, S and N, the heterocycle being optionally substitutedwith one or more identical or different Y radicals, or R₃ representsindanyl, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-benzodioxolyl,2-oxopiperidinyl or 2-(4-nitromethylcarbonyl-3-chlorophenyl)aminocarbonyl!-1-(phenyl)ethyl;

Y represents a halogen atom, C₁ -C₇ alkyl, C₁ C₇ alkoxy,trifluoromethyl, carboxy, carbamoyl, (C₁ -C₇) alkylcarbamoyl, di-(C₁-C₇) alkylcarbamoyl, C₁ -C₇ alkoxycarbonyl, amino, C₁ -C₇ -alkylamino,di-(C₁ -C₇)-alkylamino, nitro, cyano, hydroxy, trifluoromethoxy, C₃ -C₁₂cycloalkyl, sulfo, C₁ -C₇ alkylthio, C₁ -C₇ alkylsulfinyl, C₁ -C₇alkylsulfonyl, C₂ -C₈ alkylcarbonyl, C₂ -C₈ alkylthiocarbonyl, C₂ -C₈alkylcarbonylamino, or C₆ -C₁₀ aryl;

E represents a divalent radical chosen from:

(i) --CO--NR₄ -- in which the carbonyl group is linked to --(CR₁ R₂)_(p)-- and R₄ represents the radical --(CH₂)_(q) --R₅ where q is chosen from0 and 1; and where R₅ represents a hydrogen atom; a C₁ -C₇ alkyl group;a C₆ -C₁₀ aryl group or an optionally aromatic three- to ten-memberedheterocycle in which one to four ring atoms are identical or differentheteroatoms chosen from O, N and S; or R₅ and R₃ together form a bond;

(ii) --SO₂ --NR₄ -- in which the sulfonyl group is linked to --(CR₁R₂)_(p) -- and R₄ is as defined above;

(iii) --NR₄ -- in which R₄ is as defined above;

(iv) --CH═N-- in which the nitrogen atom is linked to A; and

(v) an oxygen atom;

n represents 0 or 1;

on the condition that --A(X)--(E)_(n) --(CR₁ R₂)_(p) --Z--R₃ does notrepresent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl,4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl,2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substitutedwith a group X and optionally substituted 2-fluorophenyl as definedabove, and

on the condition that when A represents pyridyl, X represents methyl andn is equal to 1, E does not represent --NR₄ --.

These compounds are inhibitors of the enzyme aldose reductase and may beused in the treatment or prevention of the complications of diabetes:neurological, peripheral and autonomous complications, renalcomplications and ocular complications such as cataract and retinopathy.

The physiologically acceptable salts of the compounds of formula (I)comprise the salts formed with metals (such as sodium, potassium,calcium, magnesium, aluminum), or with bases such as ammonium hydroxideor substituted amines (such as diethylamine, triethylamine, piperidine,piperazine, morpholine) or basic amino acids (such as lysine, arginine)or with osamines (such as meglumine) or with amino alcohols (such as3-aminobutanol, 2-aminoethanol).

The term "aryl" represents an aromatic mono- or bicyclic groupcomprising 6 to 10 carbon atoms, such as phenyl or naphthyl.

The term "heterocycle" denotes a mono- or bicyclic ring with an aromaticcharacter or otherwise, comprising 3 to 10 ring atoms of which 1 to 4are identical or different heteroatoms chosen from oxygen, sulfur andnitrogen, such as for example, the aziridinyl, oxiranyl, oxazolyl,furyl, tetrahydrofuranyl, thienyl, imidazolyl, pyridyl, pyrazinyl,benzothienyl, benzopyranyl, benzofuryl, benzothiazolyl, pyrimidinyl,pyridazinyl, piperidinyl, quinolyl, tetrahydroquinolyl, tetrazolyl,phthalazinyl, purinyl, indolyl, chromenyl, chromanyl, isochromanyl andpyrrolyl.

The term "cycloalkyl" denotes saturated hydrocarbon groups containing 3to 12 carbon atoms, preferably 3 to 8, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecenyl and cyclododecyl.

The term "halogen" represents a fluorine, chlorine, bromine or iodineatom.

The term "alkyl" denotes a linear or branched hydrocarbon radical suchas methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl,pentyl, hexyl, heptyl.

The term "alkoxy" denotes an alkyl group linked to an oxygen atom.Examples thereof are the methoxy, ethoxy, isopropyloxy, butoxy, hexyloxyradicals.

Likewise, "aryloxy" denotes an aryl radical as defined above linked toan oxygen atom, such as phenoxy and naphthyloxy.

According to the invention, "alkenylene" radical is understood to mean,moreover, a divalent hydrocarbon radical carrying one or more ethylenicdouble bonds such as, for example, --CH═CH--CH₂ -- or --CH═CH--CH═CH--.

"Carbamoyl" radical denotes the monovalent radical of formula --CO--NH₂.The radical "(C₁ -C₇)alkylcarbamoyl" denotes a carbamoyl radicalsubstituted with a C₁ -C₇ alkyl group on the nitrogen atom and theradical "di-(C₁ -C₇)alkylcarbamoyl" denotes a carbamoyl radicalsubstituted on the. nitrogen atom with two C₁ -C₇ alkyl groups.

The radical "(C₁ -C₇)alkoxycarbonyl" denotes a radical R--C--CO-- inwhich R represents a C₁ -C₇ alkyl group.

The radical "(C₁ -C₇)alkylamino" denotes an amino group substituted onthe nitrogen atom with a (C₁ -C₇)alkyl radical and the radical "di-(C₁-C₇)alkylamino" denotes an amino group substituted on the nitrogen atomwith two (C₁ -C₇)alkyl radicals.

The terms "alkylthio", "alkylsulfinyl" and "alkylsulfonyl" represent analkyl group linked to a sulfur atom which is respectively nonoxidized,monooxidized or di-oxidized, such as methylthio, methylsulfinyl ormethylsulfonyl.

Some compounds related to this type are known. For example, DE 2,415,350describes antiallergic compounds of formula: ##STR3## in which R₁, R₂,R₃, R₄, which are identical or different, may represent a hydrogen orhalogen atom, an alkyl, alkoxy, aryl or arylalkyl group, a heterocycleor, two by two, a carbocycle or a heterocycle.

In patent DE 2,741,011, antihistaminic-antiallergic compounds aredescribed, which are of the formula: ##STR4## in which R^(o) representsa hydrogen atom, a (C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl, (C₃-C₆)cycloalkyl-(C₁ -C₂)alkyl, (C₃ -C₆)alkenyl or (C₃ -C₆)alkynyl groupor a radical of formula ##STR5##

Nitromethyl ketone derivatives attached to polysubstitutednaphthyridines and quinolones are described in patent EP 574 231 for anantibiotic activity.

Other nitromethyl ketone derivatives have been described in theliterature, for example as synthesis intermediates, but the prior artdoes not refer at all to a potential therapeutic use of these compounds.There may be mentioned for example J. SETER, Israel J. Chem (1966) 4,7-22 or BAKER D. C. and PUTT S. R., Synthesis (1978) 678-9 or FIELD G.F. and ZALLY W. J., Synthesis (1979) 295-6 or HAMADA Yasumasa et al.,Chem. Pharm. Bull (1981) 29, 259-61.

The known nitromethyl ketone derivatives do not correspond to theformula (I) of the compounds of the invention; moreover, none of thesecompounds is described as having any inhibitory activity towards aldosereductase.

Preferred compounds of the invention are those for which, in the formula(I):

A represents phenyl, n and p represent 0, Z represents a bond and R₃represents a hydrogen atom, or

A represents phenyl, n represents 1 and E represents --CO--NR₄ --, andmore particularly those for which p represents 1, R₁ and R₂ represent ahydrogen atom and Z represents a bond; or

A represents phenyl, n represents 1, E represents --SO₂ --NR₄ --; or

A represents phenyl, n is equal to 1, E represents --CO--NR₄ --, p isequal to 0 and Z represents --SO₂ --NH--; or

A represents an aromatic heterocycle such as benzothienyl or thienyl; or

A represents naphthyl; or

n represents 1 and E represents an oxygen atom.

Another group of preferred compounds consists of the compounds offormula: ##STR6## in which A represents phenyl, naphthyl, benzothienylor thienyl;

X represents halogen, cyano, C₁ -C₇ alkyl, trifluoromethyl, C₂ -C₇alkoxy or trifluoromethoxy;

R₁ and R₂ represent a hydrogen atom, or R₁ and R₂ together form analkylene chain of the --(CH₂)_(r) -- type, where r is chosen from 2, 3and 4;

p is chosen from 0, 1, 2 and 3;

Z represents a bond, the divalent radical --CO--NH-- in which thecarbonyl function is linked to R₃ or the divalent radical --SO₂ --NH--in which the sulfonyl function is linked to R₃ ;

R₃ represents a hydrogen atom, C₁ -C₇ alkyl optionally substituted withone or more identical or different Y radicals; phenyl optionallysubstituted with one or more identical or different Y radicals; phenoxyoptionally substituted with one or more identical or different Yradicals; C₃ -C₁₂ cycloalkyl optionally substituted with one or moreidentical or different Y radicals; benzothienyl; benzofuryl; or R₃represents 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl or 2-oxopiperidinyl;

Y represents a halogen atom, C₁ -C₇ alkoxy, trifluoromethyl, carboxy,trifluoromethoxy or phenyl;

E represents a divalent radical chosen from:

(i) --CO--NR₄ in which the carbonyl group is linked to --(CR₁ R₂)_(p) --and R₄ represents the radical (CH₂)_(q) --R₅ where q is chosen from 0and 1, and where R₅ represents a hydrogen atom, a C₁ -C₇ alkyl group ora phenyl group;

(ii) --SO₂ --NR₄ -- in which the sulfonyl group is linked to --(CR₁R₂)_(p--) and R₄ is as defined above;

(iii) --NR₄ -- in which R₄ is as defined above;

(iv) --CH═N-- in which the nitrogen atom is linked to A; and

(v) a hydrogen atom;

n represents 0 or 1;

on the condition that --A(X)--(E)_(n) --(CR₁ R₂)_(p) --Z--R₃ does notrepresent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl,4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl,2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substitutedwith a group X and optionally substituted, 2-fluorophenyl as definedabove, and

on the condition that when A represents pyridyl, X represents methyl andn is equal to 1, E does not represent --NR₄ --, as well as theiraddition salts with pharmaceutically acceptable bases.

Among the preferred compounds of the invention, there may be mentioned:

(1) nitromethyl 2-trifluoromethoxyphenyl ketone;

(2) nitromethyl 2-cyanophenyl ketone;

(3) nitromethyl 2-ethylphenyl ketone;

(4) nitromethyl 2-trifluoromethylphenyl ketone;

(5) nitromethyl 2-ethoxyphenyl ketone;

(6) nitromethyl 2-isopropyloxyphenyl ketone;

(7) nitromethyl 2-methyl-1-naphthyl ketone;

(8) nitromethyl 3-chloro-2-naphthyl ketone;

(9) nitromethyl 3-chlorobenzo b!thien-2-yl ketone;

(10) nitromethyl 6-methoxy-5-trifluoromethyl-1-naphthyl ketone;

(11) 4-methyl-N- 2-nitromethylcarbonyl-3-methylbenzob!thien-5-yl!benzenesulfonamide;

(12) N- 3-chloro-4-nitromethylcarbonylphenyl!acetamide;

(13) nitromethyl 4-amino-2-chlorophenyl ketone;

(14) N- 3-chloro-4-nitromethylcarbonylphenyl!benzamide;

(15) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-chlorobenzamide;

(16) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-methylbenzamide;

(17) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-methoxybenzamide;

(18) N-3-chloro-4-nitromethylcarbonylphenyl!-2-trifluoromethylbenzamide;

(19) N-3-chloro-4-nitromethylcarbonylphenyl!-2,2,3,3-tetramethylcyclopropanecarboxamide;

(20) N- 3-chloro-4-nitromethylcarbonylphenyl!hexaneamide;

(21) N- 3-chloro-4-nitromethylcarbonylphenyl!cyclopentylacetamide;

(22) N- 3-chloro-4-nitromethylcarbonylphenyl!-3-phenylpropaneamide;

(23) N- 3-chloro-4-nitromethylcarbonylphenyl!-2-phenylpropaneamide;

(24) N- 3-chloro-4-nitromethylcarbonylphenyl!phenylacetamide;

(25) N- 3-chloro-4-nitromethylcarbonylphenyl!benzob!-thienyl-2-carboxamide;

(26) N- 3-chloro-4-nitromethylcarbonylphenyl!benzofuryl-2-carboxamide;

(27) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-chlorophenoxyacetamide;

(28) 2-chloro-N- 3-chloro-4-nitromethylcarbonylphenyl!phenylacetamide;

(29) N-3-chloro-4-nitromethylcarbonylphenyl!-1-(4-chlorophenyl)cyclopropylcarboxamide;

(30) N-3-chloro-4-nitromethylcarbonylphenyl!-2-trifluoromethylphenylacetamide;

(31) N-3-chloro-4-nitromethylcarbonylphenyl!-4-chlorobenzenesulfonamide;

(32) N- 3-chloro-4-nitromethylcarbonylphenyl!benzenesulfonamide;

(33) nitromethyl 4- N,N-di(phenylmethyl)amino!-2-chlorophenyl ketone;

(34) N- 2-chloro-3-nitromethylcarbonylphenyl!acetamide;

(35) N- 2-chloro-3-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(36) N- 4-chloro-3-nitromethylcarbonylphenyl!acetamide;

(37) N- 4-chloro-3-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(38) N- 4-chloro-3-nitromethylcarbonylphenyl!benzenesulfonamide;

(39) 2-3-chloro-4-nitromethylcarbonylphenylaminocarbonylmethylaminocarbonyl!benzoicacid;

(40) N-3-chloro-4-nitromethylcarbonylphenyl!-1,3-dihydro-1,3-dioxo-2H-isoindol-2-ylacetamide

(41) 1- 3-chloro-4-nitromethylcarbonylphenyl!-3-phenylsulfonylurea;

(42) nitromethyl 3-methyl-2-thienyl ketone;

(43) N- 3-chloro-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(44) N- 3-chloro-4-nitromethylcarbonylphenyl!-2-oxopiperidine;

(45) N-3-chloro-4-nitromethylcarbonylphenyl!-1-(4-chlorophenyl)cyclopentanecarboxamide;

(46) N- 3-chloro-4-nitromethylcarbonylphenyl!indan-2-ylacetamide;

(47) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-chlorophenylacetamide;

(48) N- 3-chloro-4-nitromethylcarbonylphenyl!-3-chlorophenylacetamide;

(49) N-3-chloro-4-nitromethylcarbonylphenyl!-3,4-dichlorophenylacetamide;

(50) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-methylphenylacetamide;

(51) N- 3-chloro-4-nitromethylcarbonylphenyl!-3-methylphenylacetamide;

(52) N-3-chloro-4-nitromethylcarbonylphenyl!-3,4-dimethylphenylacetamide;

(53) N-3-chloro-4-nitromethylcarbonylphenyl!-4-trifluoromethylphenylacetamide;

(54) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-methoxyphenylacetamide;

(55) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-nitrophenylacetamide;

(56) N-3-chloro-4-nitromethylcarbonylphenyl!-2-fluoro-4-bromophenylacetamide;

(57) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-fluorophenylacetamide;

(58) N- 3-chloro-4-nitromethylcarbonylphenyl!-3-phenyl-2-propeneamide;

(59) N- 3-methyl-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(60) N- 2-bromo-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(61) nitromethyl 2-chloro-4-methoxyphenyl ketone;

(62) nitromethyl 2-isopropylphenyl ketone;

(63) N- 4-chloro-2-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(64) nitromethyl 2-chloro-4-phenylthiophenyl ketone;

(65) N- 3-chloro-4-nitromethylcarbonylphenyl!-4-3-chloro-4-nitromethylcarbonylphenylaminocarbonyl!-3-phenylbutaneamide;

(66) nitromethyl 2-chloro-4-phenylsulfinylphenyl ketone;

(67) nitromethyl 4-chloro-2-trifluoromethoxyphenyl ketone;

(68) N-2-(3-chloro-4-nitromethylcarbonylphenylethyl)!-2-methylbenzenesulfonamide;

(69) N- 3-bromo-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide;

(70) N-3-chloro-4-nitromethylcarbonylphenyl!-N-isopropylbenzenesulfonamide.

The compounds of the invention are for example prepared according to thefollowing methods (A) and (B):

(A) The products of formula (I) may be prepared from the carboxylicacids (II) ##STR7## by the action of di-(C₁ -C₇)alkyl cyanophosphonateand nitromethane in the presence of a base in a solvent which is inerttowards the reaction, preferably in a polar aprotic solvent such asdimethylformamide or tetrahydrofuran. Advantageously, the molar ratio ofthe carboxylic acid of formula (II) to the nitromethane varies between0.6/1 and 2/1, preferably between 0.8/1 and 1.2/1. As base, use ispreferably made of an amine, an alkyllithium, an alkali metal hydride,an alkali metal carbonate, an alkali metal hydroxide or an alkali metalalcoholate and especially triethylamine, pyridine, butyllithium, sodiumhydride, potassium carbonate, potassium hydroxide or potassiumtertbutoxide in a ratio of the carboxylic acid of formula (II) to thebase of between 0.2/1 and 0.5/1, or better still in a ratio of 0.4/1.

The reaction temperature is generally between -78° C. and the refluxtemperature of the solvent and preferably between -5° C. and 80° C.Generally, the reaction is continued for 2 to 72 hours, preferably for 2to 18 hours.

(B) As a variant, the product of formula (I) may be prepared from thecarboxylic acids of formula (II) by prior conversion to the phenyl esterof formula (III) according to the following reaction scheme: ##STR8## a)The preparation of the phenyl esters (III) may be carried out byreacting successively or simultaneously SOCl₂, or POCl₃, and phenol inthe absence or in the presence of a solvent which is inert towards thereaction. When a solvent is used, it is preferably an aprotic solventsuch as dichloromethane, benzene or toluene. In this first step, themolar ratio of SOCl₂, respectively POCl₃, to the carboxylic acid offormula (II) is preferably between 1/1 and 50/1, or better still theratio is 10/1. Likewise, it is preferable that the molar ratio of thecarboxylic acid to the phenol is between 1/0.9 and 1/1.2, or betterstill this ratio is 1/1.05. The reaction temperature is advantageouslybetween -78° C. and the reflux temperature of the solvent, preferablybetween 0° C. and the reflux temperature of the solvent. This reactionis continued for 1 to 48 hours, preferably for 1 to 8 hours.

b) The phenyl esters of formula (III) thus formed are then treated withnitromethane in the presence of a base at a temperature of between 20°C. and the boiling point of the solvent and, preferably, between 20° C.and 40° C. The duration of the reaction varies advantageously between 2and 72 hours, preferably between 2 and 48 hours. For this stage, themolar ratio of the compound of formula (III) to the nitromethane will beset at between 1/1 and 1/5, this ratio being preferably equal to 1/3. Asappropriate base, there will be used for example an alkali metalhydroxide, an alkali metal carbonate, an alkali metal hydride, analkyllithium, an amine or an alkali metal alcoholate. Thus, the base maybe, for example, selected from potassium tert-butoxide, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium hydride,butyllithium and pyridine. The molar ratio of the phenyl ester offormula (III) to the base will be advantageously between 1/1 and 1/5,this ratio being preferably equal to 1/3.

Other procedures allow the preparation of the compounds of formula (I).

When in the formula (I) above, n is equal to 1 and E represents--CO--NR₄ --, the compounds of the invention may be obtained by reactingan acid halide of formula R₃ --Z--(CR₁ R₂)_(p) --CO--hal where R₁, R₂,R₃, Z and p are as defined above and hal is a halogen atom, with anamine of formula (IV): ##STR9## in which A and X are as defined above.

The procedure is carried out in the presence of a base, preferably anamine, such as pyridine, triethylamine or dimethylaminopyridine, in asolvent, preferably an aprotic solvent, at a temperature of between -20°C. and the reflux temperature of the solvent, for example between 0 and40° C. The duration of the reaction is between 2 and 48 hours.

Examples of preferred solvents are dichloro-methane, tetrahydrofuran,benzene or toluene.

When, in the formula (I) above, n is equal to 1 and E represents --SO₂--NR₄ --, the compounds of the invention may be obtained by reacting asulfonyl halide of formula R₃ --Z--(CR₁ R₂)_(p) --SO₂ --hal where R₁,R₂, R₃, Z and p are as defined above and hal is a halogen atom, with anamine of formula (IV) as defined above. Here again, the procedure isadvantageously carried out in the presence of a base in a solvent at atemperature of between -20° C. and the reflux temperature of thesolvent. The preferred operating conditions are the same as for thereaction of the acid chloride with the amine of formula (IV) above.

As a variant, it is possible, in a first instance, to synthesize thebenzyl ester of formula (III): ##STR10## according to one of thereaction steps (i) to (vi) below, and then to treat the benzyl ester offormula (III) by the action of nitromethane in the presence of a base asdescribed above:

step (i) when n is equal to 1 and E represents --CO--NR₄ --, an acidhalide of formula R₃ --Z--(CR₁ R₂)_(p) --CO--hal, where R₁, R₂, R₃, Zand p are as defined above and hal is a halogen atom, is reacted with anamine of formula (V): ##STR11## in which A and X are as defined above;or step (ii) when n is equal to 1 and E represents --SO₂ --NR₄ --, asulfonyl halide of formula R₃ --Z--(CR₁ R₂)_(p) --SO₂ --hal, where R₁,R₂, R₃, Z and p are as defined above and hal is a halogen atom, isreacted with an amine of formula (V) as defined above; or

step (iii) when n is equal to 1 and E represents --NR₄ --, a compound offormula R₃ --Z--(CR₁ R₂)_(p) --hal, where R₁, R₂, R₃, Z and p are asdefined above and hal is a halogen atom, is reacted with an amine offormula (V) as defined above; or

step (iv) when n is equal to 1 and E represents --CH═N--, an aldehyde offormula R₃ --Z--(CR₁ R₂)_(p) --CHO, where R₁, R₂, R₃, Z and p are asdefined above, is reacted with an amine of formula (V) as defined above;or

step (v) when n is equal to 1 and E represents --O--, a compound offormula R₃ --Z--(CR₁ R₂)_(p) --hal, where R₁, R₂, R₃, Z and p are asdefined above and hal is a halogen atom, is reacted with an alcohol offormula (VI): ##STR12## in which A and X are as defined above; step (vi)when n is equal to 1, E represents --CO--NR₄ --, p is 0 and Z represents--SO₂ --NH--, an isocyanate of formula R₃ --SO₂ --N═C═O, in which R₃ isas defined above, is reacted with an amine of formula (V) as definedabove;

step (vii) when n is equal to 1 and E represents --CO--NR₄ --, an acidof formula R₃ --Z--(CR₁ R₂)_(p) --COOH, where R₁, R₂, R₃, Z and p are asdefined above, is reacted with an amine of formula (V) as defined above.

Some compounds of formula (I) may be obtained from compounds of formula(I) using simple conversion steps.

Thus, the compounds of formula (I) in which n is equal to 1, Erepresents --CO--NH--, p represents 1, R₁ and R₂ represent a hydrogenatom, Z represents a bond and R₃ represents1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl may be prepared from thecorresponding compounds (having meanings of A and X which are identical)in which n is equal to 1, E represents --CO--NH--, p represents 1, R₁and R₂ represent a hydrogen atom, Z represents --CO--NH-- and R₃represents 2-carboxyphenyl, by the action of hydrochloric acid.

Likewise, the compounds in which n represents 1, E represents--CO--NH--, --(CR₁ R₂)_(p) -- represents CH₂ and R₃ represents 2-(4-nitromethylcarbonyl-3-chlorophenyl)-aminocarbonyl!-1-(phenyl)ethylmay be prepared by reacting the dichloride of formula

    Cl--CO--CH.sub.2 --CH(C.sub.6 H.sub.5)--CH.sub.2 --CO--Cl

with two equivalents of the ester of formula

    NH.sub.2 --A(X)--COOC.sub.6 H.sub.5

in the presence of a base, and then treating the compound obtained withnitromethane in the presence of a base.

The compounds of formula (IV) are easily synthesized from commerciallyavailable compounds by methods known in the art.

By way of example, the compounds of formula (IV) may be obtained fromthe corresponding amines of formula (VII):

    NH.sub.2 --A(X)COOPh                                       (VII)

according to a procedure comprising the steps consisting of:

protecting the amino function with a protective group such as a (C₁-C₇)alkylcarbonyl group,. for example acetyl;

reacting the amine thus protected with di(C₁ -C₇)alkyl cyanophosphonateand nitromethane in the presence of a base; and then

deprotecting the amino function, for example by the action of sodiumhydroxide when the protective group is an acetyl group.

The capacity of the compounds of the invention to inhibit the enzymealdose reductase and to prevent the accumulation of sorbitol may bedemonstrated during standard laboratory tests below:

1) Study in vitro: inhibition of aldose reductase

The aldose reductase used is obtained from male Wistar rat crystallinelenses according to a modification of the method of S. HAYMAN et al.(Journal of Biological Chemistry 240, p. 877, 1965). The enzymaticextract is diluted in a phosphate buffer in the presence of NADPH andvarious concentrations of the test products. The reaction is initiatedwith L-glyceraldehyde and the reaction rate is measured by monitoringthe disappearance of NADPH by spectrophotometry at 340 nm. The reactionrate is calculated for each product concentration and then theconcentration necessary for a 50% reduction in the reaction rate (IC₅₀)is evaluated by linear interpolation. The results are presented in Table1 below.

2) Study in vivo: reduction of sorbitol accumulation

200 to 250 g male Wistar rats are made diabetic by intravenous injectionof streptozotocin (60 mg/kg). They then receive an oral treatment of thetest products, in the form of a suspension, 4 hours, 30 hours and 52hours after the injection of streptozotocin. Eighteen hours after thelast oral treatment, the rats are stunned and decapitated and then theirsciatic nerves are removed. After extraction, the sorbitol level in thenerves is measured according to the enzymatic method described by H. U.BERGMEYER (Methods of enzymatic analysis. H. U. BERGMEYER ed., AcademicPress New York 3, p. 1323, 1974).

The percentage protection is calculated for each product relative to thebatch of diabetic animals taking into account the sorbitol level in thesciatic nerves of nondiabetic rats.

By way of example, the results obtained for some of the test productsare given in the following table:

                  TABLE 1    ______________________________________                            Protection against               Inhibition of aldose                            increase in sorbitol               reductase in vitro                            after administration    Example No.               IC.sub.50 (nm)                            10 mg/kg/d (%)    ______________________________________     1         41           70    23         7            40    24         7            45    28         7            58    30         7            61    43         7            70    59         6            52    ______________________________________

The compounds of the invention may be used by way of medicaments asaldose reductase inhibitors, and are especially useful in the treatmentof the complications of diabetes such as cataracts, retinopathies,neuropathies, nephropathies and certain vascular diseases. The dailydosages may vary from 5 mg to 200 mg of active ingredient, for example.

These medicaments may be administered by the oral route in the form oftablets, gelatin capsules or granules affording immediate release orcontrolled release, by the intravenous route in the form of aninjectable solution, by the transdermal route in the form of an adhesivetransdermal device, by the local route in the form of a collyrium,solution, cream or gel.

A solid medicament for oral administration containing a compound of thepresent invention as active ingredient is prepared by supplementing thesaid compound with a filler and, where appropriate, a binder, adisintegrating agent, a lubricant, a coloring or a taste enhancer, andby forming the mixture into a tablet, a coated tablet, a granule, apowder or a capsule.

Examples of a filler comprise lactose, maize starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide, and examples of abinder comprise poly(vinyl alcohol), poly(vinyl ether), ethyl cellulose,methyl cellulose, acacia, tragacanth gum, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of lubricants comprise magnesium stearate,talc, poyethylene glycol, silica and hardened vegetable oils. Thecoloring may be any of those permitted for use in medicaments. Examplesof taste enhancers comprise cocoa powder, mint in herb form, aromaticpowder, mint in oil form, borneol and cinnamon powder. Of course, thetablet or granule may be suitably coated with sugar, gelatin and thelike.

An injectable form containing the compound of the present invention asactive ingredient is prepared, where appropriate, by mixing the saidcompound with a pH regulator, a buffering agent, a suspending agent, asolubilizing agent, a stabilizer, a tonic agent and/or a preservative,and by converting the mixture to a form injectable by the intravenous,subcutaneous or intramuscular route, according to a conventionalprocess. Where appropriate, the injectable form obtained may befreeze-dried by a conventional process.

Examples of suspending agents comprise methyl cellulose, polysorbate 80,hydroxyethylcellulose, acacia, tragacanth gum powder, sodiumcarboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of a solubilizing agent comprise castor oil solidified withpolyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitanmonolaurate and the ethyl ester of castor oil fatty acid.

In addition, the stabilizer comprises sodium sulfite, sodium metasulfiteand ether, whereas the preservative comprises methyl p-hydroxybenzoate,ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

A few pharmaceutical formulations are given below by way of nonlimitingexamples:

    ______________________________________     Composition of an immediate-release tablet                               100 mg     .sup. Active ingredient     .sup. Excipients: lactose, wheat starch, polyvidone,     .sup. talc, magnesium stearate.     Composition of a controlled-release tablet                               100 mg     .sup. Active ingredient     .sup. Excipients: lactose, polyvidone, talc,     .sup. magnesium stearate, polymer (cellulose     .sup. or acrylic and methacrylic or vinyl     .sup. or glyceride derivative).     Composition of a gelatin capsule                               100 mg     .sup. Active ingredient     .sup. Excipients: lactose, wheat starch,     .sup. talc, magnesium stearate.     Composition of an ampoule of injectable solution                               200 mg     .sup. Active ingredient     .sup. Excipients: mannitol, water for injection.     Composition of a cream                                2 g     .sup. (composition per 100 g of cream)     .sup. Active ingredient     .sup. Excipients: self-emulsifiable cetylstearyl     .sup. alcohol cetylaryloctanoate, nipasol,     .sup. sorbic acid, propylene glycol, carbapol.     Composition of a collyrium                                15 mg     .sup. Active ingredient     .sup. Excipients: sodium chloride, benzalkonium     .sup. chloride, water for injection.    ______________________________________

The following examples illustrate the invention with no limitation beingimplied.

In the nuclear magnetic resonance (NMR) data, the followingabbreviations are used: s for singlet, d for doublet, t for triplet, qfor quadruplet and m for unresolved complex; the chemical shifts δ areexpressed in ppm; m.p.=represents the melting point and b.p. the boilingpoint.

The entire disclosure of all applications, patents and publications,cited above and below, and of corresponding European application No.97108369.6, filed May 23, 1997, is hereby incorporated by reference.

EXAMPLE 1 Nitromethyl 2-trifluoromethoxyphenyl ketone

a) Phenyl 2-(trifluoromethoxyphenyl)benzoate

A mixture composed of 10 g (48.5 mmol) of 2-(trifluoromethoxy)benzoicacid, 50 ml of thionyl chloride and a drop of dimethylformamide isheated under reflux for 1.5 hours. After cooling and concentrating thereaction mixture under vacuum, a residue is obtained which is stirredfor 2 hours at 100° C. in the presence of 4.75 g (50 mmol) of phenol.After cooling, the reaction medium is taken up in dichloromethane,washed with a saturated NaHCO₃ solution and then with water, dried overNa₂ SO₄ and concentrated.

After distillation, 11 g of a colorless liquid are obtained (yield=80%).

b.p.=100-110° C. (under 1 mm of Hg); NMR (CDCl₃): 7.15-7.4 (7H, m); 7.55(1H, m); 8.05 (1H, dd, J=7.8 Hz and 1.8 Hz)

b) Nitromethyl 2-trifluoromethoxyphenyl ketone

4.2 ml (75 mmol) of nitromethane are added to a solution composed of 8.5g (75 mmol) of potassium tertbutoxide and 115 ml of dimethyl sulfoxide,maintained at 15° C. The mixture is stirred for 1 hour at 15° C. beforeadding, dropwise, 7 g (25 mmol) of the phenyl ester obtained in step a)above. After stirring for 3 hours at 15-20° C., 68 ml of ice-cold waterand 6.8 ml of concentrated hydrochloric acid are added, with stirring,before pouring into 500 ml of an ice-water mixture. The precipitateformed is drained, washed with water and with hexane, before beingdried. After recrystallization from an ethyl acetate-hexane mixture, 3 gof a cottony white solid are obtained (yield=48%).

m.p.=35-36° C.; NMR (DMSO-d₆): 6.3 (2H, s, exchangeable with CF₃ COOD);7.55 (2H, m); 7.8 (1H, m); 7.95 (1H, dd, J=7.7 Hz and 1.6 Hz).

EXAMPLES 2 to 6

By carrying out the procedure as in Example 1 (a and b), Examples 2 to 6are obtained: ##STR13## Nitromethyl 2-cyanophenyl ketone (Example 2)Nitromethyl 2-ethylphenyl ketone (Example 3)

Nitromethyl 2-trifluoromethylphenyl ketone (Example 4)

Nitromethyl 2-ethoxyphenyl ketone (Example 5)

Nitromethyl 2-isopropyloxyphenyl ketone (Example 6)

    ______________________________________    Exam-                         Compounds    ples  X          Phenyl esters                                  --CO--CH.sub.2 NO.sub.2    ______________________________________    2     --CN       J. Am. Chem. Soc.                                  m.p.=147-149° C.                     (1962) 2196-2201                                  NMR(DMSO-d.sub.6): 6.75                                  (2H, s, exchangeable                                  with CF.sub.3 COOD);                                  8.1(2H, m); 8.3(2H, m)    3     --CH.sub.2 CH.sub.3                     b.p..sub.1.2 =105-115° C.                                  m.p.=62-63° C.                     NMR(CDCl.sub.3):                                  NMR(DMSO-d.sub.6):                     1.2(3H, t, J=7.5Hz);                                  1.15(3H, t, J=7.45Hz);                     3.0(2H, q,   2.85(2H, q, J=7.45Hz);                     J=7.5Hz);    6.45(2H, s, exchange-                     7.1-7.3(5H, m);                                  able with CF.sub.3 COOD);                     7.35-7.45(3H, m);                                  7.40(2H, m); 7.6                     8.05(1H, dd, J=                                  (1H, m); 7.7(1H,                     6.6Hz and 1.3Hz)                                  dd, J=7.75Hz and                                  1.15Hz)    4     --CF.sub.3 NMR(CDCl.sub.3):                                  m.p=55-57° C.                     7.1(3H, m);  NMR(CDCl.sub.3): 5.9(2H,                     7.3(2H, m);  s, exchangeable with                     7.55(2H, m); CF.sub.3 COOD); 7.75(1H,                     7.7(1H, m);  m); 7.9(2H, m); 8.0(1H,                     7.8(1H, m)   m)    5     --OCH.sub.2 CH.sub.3                     CA 95 168816 f                                  m.p=145-148° C.                                  NMR(DMSO-d.sub.6):                                  1.6(3H, t, J=7Hz);                                  4.35(2H, q, J=7Hz);                                  6.25(2H, s,                                  exchangeable with                                  CF.sub.3 COOD); 7.25(1H,                                  m); 7.35(1H, m);                                  8.15(1H, m);                                  8.0(1H, m)    6     --OCH(CH.sub.3).sub.2                     b.p..sub.0.5 =150° C.                                  m.p.=78-80° C.                     NMR(CDCl.sub.3):                                  NMR(DMSO-d.sub.6): 1.4                     1.3(6H, d,   (6H, d; J=6Hz);                     J=6.1Hz);    4.9(1H, m, J=6Hz);                     4.6(1H, m,   6.1(2H, s, exchangeable                     J=6.1Hz);    with CF.sub.3 COOD);                     6.95(2H, m); 7.1(1H, m); 7.2(1H,                     7.15(3H, m); d, J=8.45Hz);                     7.35(3H, m); 7.7(1H, m);                     7.85(1H, dd, 7.9(1H, dd,                     J=7.7Hz      J=7.85Hz and 1.8Hz)                     and 1.8Hz)    ______________________________________

EXAMPLES 7 to 9

By carrying out the procedure as in Example 1 (a and b), the compoundsof Examples 7 to 9 are obtained: ##STR14## where R represents R₃--Z--(CR₁ R₂)_(p) --(E)_(n) --Nitromethyl 2-methyl-1-naphthyl ketone(Example 7)

Nitromethyl 3-chloro-2-naphthyl ketone (Example 8)

Nitromethyl 3-chlorobenzo b!thien-2-yl ketone (Example 9)

    ______________________________________    Exam- ples          0 #STR15##   Phenyl esters                                   Compounds --CO--CH.sub.2 NO.sub.2    ______________________________________          1 #STR16##   m.p.=65-69° C. NMR(CDCl.sub.3): 1.6(3H, s);                       7.2-7.5(8H, m); 7.8(2H, m); 7.95(1H,                                   m.p.=126-128° C. NMR(CDCl.sub.3):                                   2.5(3H, s); 5.9(2H, s, exchangeable with                                   CF.sub.3 COOD); 7.4(2H, m); 7.7(2H, m);                                   8.0(1H, m); 8.6(1H, d, J=0.5Hz)    8          2 #STR17##   NMR(DMSO-d.sub.6): 7.3(3H, m); 7.5(2H, m); 7.7(2H, m);                       8.0(1H, d, J=8.1Hz); 8.15(1H, d, J= 8Hz); 8.2(1H, s);                       8.8(1H, s)  m.p.=109-113° C. NMR(DMSO-d.sub.6):                                   6.6(2H, s, exchangeable with CF.sub.3                                   COOD); 7.7(2H, m); 8.0(2H, m); 8.25(1H,                                   s); 8.65(1H, s)    9          3 #STR18##   Z. Chem (1997) 17,133-134                                   m.p.=158-160° C. NMR(DMSO-d.sub.6):                                   6.65(2H, s, exchangeable with CF.sub.3                                   COOD); 7.8(2H, m); 8.15(1H, dd, J=7.9Hz                                   and 0.8Hz; 8.3(1H, d, J=7.9Hz)    ______________________________________

EXAMPLES 10 and 11

By carrying out the procedure as in Example 1 (a and b), the compoundsof Examples 10 and 11 are obtained: ##STR19## where R represents R₃--Z--(CR₁ R₂)_(p) --(E)_(n) --Nitromethyl6-methoxy-5-trifluoromethyl-1-naphthyl ketone (Example 10)

4-Methyl-N- 2-nitromethylcarbonyl-3-methylbenzob!-thien-5-yl!benzenesulfonamide (Example 11)

    ______________________________________    Exam- ples          0 #STR20##   Phenyl esters                                   Compounds --CO--CH.sub.2 NO.sub.2    ______________________________________    10          4 #STR21##   m.p. 137-139° C. NMR(DMSO-d.sub.6): 4.1(3H, 3);                       7.3-7.5(3H, m); 7.6(2H, m); 7.85(2H, m); 8.4(2H, m);                       9.1(1H, d, J=9.75Hz)                                   m.p. 146-148° C. NMR(DMSO-d.sub.6):                                   4.05(3H, s); 6.6(2H, s); 6.6(2H, s,                                   exchangeable with CF.sub.3 COOD); 7.8(2H,                                   m); 8.15(1H, d, J=7Hz) - # 8.35(1H, m);                                   8.85(1H, d, J=9.75Hz)    11          5 #STR22##   NMR(DMSO-d.sub.6) 2.35(3H, s); 2.7(3H, s); 2.7(3H, s);                       6.8(4H, m); 7.1-7.6(5H, m) 7.9(2H, m); 8.0(1H, m);                       10.5(1H, s, exchangeable with CF.sub.3 COOD)                                   m.p. 185-190° C. NMR(DMSO-d.sub.6):                                   2.3(3H, s); 2.6(3H, s); 6.45(2H, s                                   exchange- able with CF.sub.3 COOD);                                   7.3(3H, m)7.7(3H, m); - # 7.9(1H, d,                                   J=8.75Hz); 10.45(1H, s, ex- changeable                                   with CF.sub.3 COOD)    ______________________________________

EXAMPLE 12 N- 3-Chloro-4-nitromethylcarbonylphenyl!acetamide

a) Phenyl 4-amino-2-chlorobenzoate

30 g of phenyl 2-chloro-4-nitrobenzoate prepared according to MakotoSuzuki, Yakugaku Zasshi (1959) 79, 286-90 (CA 53 14991 f) are added to amixture of 800 ml of water, 60 ml of acetic acid and 96.5 g (1.728 mol)of iron. The reaction medium is heated for 1 hour under reflux. Aftercooling, the reaction medium is filtered and the solid recovered iswashed with ethyl acetate. The aqueous phase is saturated with NaClbefore being extracted with ethyl acetate. The combined organic phasesare concentrated and purified by chromatography on a silica column withCH₂ Cl₂ (yield=82%).

m.p.=127-128° C.; NMR (DMSO-d₆): 6.35 (2H, s, exchangeable with CF₃COOD); 6.55 (1H, dd, J=8.6 Hz and 2.2 Hz); 6.7 (1H, d, J=2.2 Hz);7.1-7.3 (3H, m); 7.45 (2H, m); 7.9 (1H, d, J=8.6 Hz).

b) Phenyl 4-(acetylamino)-2-chlorobenzoate

37 ml (266 mmol) of triethylamine are added to a mixture composed of 60g (242 mmol) of the amine obtained in step a) above and of 280 ml ofdichloromethane, followed by 20.6 ml (290 mmol) of acetyl chloride.After stirring for 2 hours at room temperature, the medium is heated for2 hours under reflux. After cooling, the reaction medium is thrown overan icehydrochloric acid mixture. The organic phase is decanted off andthe aqueous phase is extracted with dichloromethane. The combinedorganic phases are washed with water, dried over Na₂ SO₄ andconcentrated, to give an oil which crystallizes. (Yield=quantitative)

m.p.=84-86° C.; NMR (DMSO-d₆): 2.15 (3H, s); 7.35 (3H, m); 7.5 (2H, m);7.7 (1H, dd, J=8.7 Hz and 2 Hz); 8.05 (1H, d, J=2 Hz); 8.2 (1H, d, J=8.7Hz); 10.5 (1H, s, exchangeable with CF₃ COOD).

c) N- 3-chloro-4-nitromethylcarbonylphenyl!acetamide

The title compound was obtained by carrying out the procedure as inExample lb from the compound prepared in the preceding step b).

m.p.=196° C. (decomposition); NMR (DMSO-d₆): 2.3 (3H, s); 6.55 (2H, s,exchangeable with CF₃ COOD); 7.8 (1H, dd, J=8.7 Hz and 1.8 Hz); 8.1 (2H,m); 10.7 (1H, s, exchangeable with CF₃ COOD).

EXAMPLE 13 Nitromethyl 4-amino-2-chlorophenyl ketone

A mixture of 12.2 g (47.5 mmol) of N-3-chloro-4-nitromethylcarbonylphenyl!acetamide prepared in Example 12,11 g (274 mmol) of sodium hydroxide pellets and 161 ml of water isheated at 80° C. for 1 hour. After cooling, the reaction medium isdiluted with 900 ml of water and acidified to pH 5 by adding aceticacid. The precipitate formed is recovered, washed with water andair-dried before being recrystallized from ethyl acetate (Yield=27%).

m.p.=131-133° C.; NMR (DMSO-d₆): 6.1 (2H, s, exchangeable with CF₃COOD); 6.45 (3H, m, of which 2H are exchangeable with CF₃ COOD); 6.55(1H, d, J=2 Hz); 7.5 (1H, d, J=8.75 Hz).

EXAMPLE 14 N- 3-Chloro-4-nitromethylcarbonylphenyl!benzamide

a) Phenyl 2-chloro-4- (benzoyl)amino!benzoate

A solution of 2.27 g (16.1 mmol) of benzoyl chloride in 30 ml ofdichloromethane is added dropwise to a mixture composed of 4 g (16.1mmol) of the compound prepared in Example 12a, of 2.26 ml (17.7 mmol) oftriethylamine and 40 ml of dichloromethane, maintained at 0° C. Thereaction medium is stirred for 1 hour at 0° C. and then for 48 hours atroom temperature. The dichloromethane is evaporated off. The residue istaken up in water, the solid filtered, washed with water and dried undervacuum at 80° C., to give 5 g of an off-white powder (Yield=89%).

m.p.=126-128° C.; NMR (DMSO-d₆): 7.3 (3H, m); 7.5-7.7 (5H, m); 8.0 (3H,m); 8.2 (2H, m); 10.8 (1H, s, exchangeable with CF₃ COOD).

b) N- 3-chloro-4-nitromethylcarbonylphenyl!benzoate

Obtained by carrying out the procedure as in Example 1b (Yield=57%).

m.p.=165-167° C.; NMR (DMSO-d₆): 6.6 (2H, s, exchangeable with CF₃COOD); 7.7-7.8 (3H, m); 8.1 (4H, m); 8.3 (1H, d, J=0.8 Hz); 10.9 (1H, s,exchangeable with CF₃ COOD).

EXAMPLES 15 to 27

The compounds of Examples 15 to 27 were obtained from the amine preparedin Example 12a, the procedure being carried out as in Example 14.##STR23## N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-chlorobenzamide(Example 15) N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-methylbenzamide(Example 16)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-methoxybenzamide (Example 17)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-2-trifluoromethylbenzamide(Example 18)

N-3-Chloro-4-nitromethylcarbonylphenyl!-2,2,3,3-tetramethylcyclopropanecarboxamide(Example 19)

N- 3-Chloro-4-nitromethylcarbonylphenyl!cyclopentylacetamide (Example20)

N- 3-Chloro-4-nitromethylcarbonylphenyl!hexaneamide (Example 21)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-3-phenylpropaneamide (Example22)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-2-phenylpropaneamide (Example23)

N- 3-Chloro-4-nitromethylcarbonylphenyl!phenylacetamide (Example 24)

N- 3-Chloro-4-nitromethylcarbonylphenyl!benzo b!-thienyl-2-carboxamide(Example 25)

N- 3-Chloro-4-nitromethylcarbonylphenyl!benzofuryl-2-carboxamide(Example 26)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-chlorophenoxyacetamide(Example 27).

    __________________________________________________________________________         R3--Z--              Compounds    Examples         (CR.sub.1 R.sub.2).sub.p                   Phenyl esters                              --CO--CH.sub.2 NO.sub.2    __________________________________________________________________________    15         1 #STR24##                   m.p. 183-186° C. NMR (DMSO-d.sub.6): 7.35(3H, m);                   7.55(2H, m); 7.7(2H, d, J = 8.6Hz); 8.0(1H, dd, J = 8.7Hz                   and 2Hz); 8.05(2H, m); 8.25(2H, m); 10.8(1H, s, ex-                   changeable with CF.sub.3 COOD)                              m.p. 151-154° C. NMR (DMSO-d.sub.6):                              6.6(2H, s, exchange- able with CF.sub.3 COOD);                              7.9(2H, d, J = 8.6Hz); 8.15(4H, m); 8.3(1H, d,                              J = 1.85Hz); 10.1(1H, s, exchange- able with                              CF.sub.3 COOD)    16         2 #STR25##                   m.p. 151-152° C. NMR (DMSO-d.sub.6): 2.45(3H, s);                   7.35-7.55(7H, m); 8.0(3H, m); 8.25(2H, m); 10.7(1H, s, ex-                   changeable with CF.sub.3 COOD)                              m.p. 180-181° C. NMD (DMSO-d.sub.6):                              2.4(3H, s); 6.4(2H, s, exchange- able with                              CF.sub.3 COOD); 7.4(2H, d, J = 8Hz); 8.0(4H,m);                              8.15(1H, d, J = 1.7Hz); 10.65 (1H, s,                              exchangeable with CF.sub.3 COOD)    17         3 #STR26##                   m.p. 128-131° C. NMR (DMSO-d.sub.6): 3.90(3H, s);                   7.15(2H, d, J = 8.9Hz);  7.35(3H, m); 7.55(2H, m); 8.0(3H,                   m); 8.2(2H, m); 10.6(1H, s, ex- changeable with CF.sub.3                   COOD)      m.p. 189-190° C. NMR (DMSO-d.sub.6):                              3.95(3H, s); 6.5(2H, s, exchange- able with                              CF.sub.3 COOD); 7.2(2H, d, J = 8.8Hz); 8.05(4H,                              m), 8.25(1H, d, J = 1.7Hz); 10.7(1H, s,                              exchange- able with CF.sub.3 COOD)    18         3 #STR27##                   m.p. 150-152° C. NMR (DMSO-d.sub.6): 7.5(3H, m);                   7.65(2H, m); 7.9-8.05(5H, m); 8.2(1H, d, J = 1.9Hz);                   8.3(1H, d, J = 8.6Hz); 11.3(1H, s, ex- changeable with                   CF.sub.3 COOD)                              m.p. 199-201° C. NMR (DMSO-d.sub.6):                              6.7(2H, s, exchange- able with CF.sub.3 COOD);                              8.0-8.3(7H, m); 11.4(1H, s, exchange-  able                              with CF.sub.3 COOD)    19         4 #STR28##                   NMR (DMSO-d.sub.6): 1.2(6H, s); 1.25(6H, s); 7.3(3H, m);                   7.5(2H, m); 7.6(1H, dd, J = 8.7Hz and 2.1Hz); 8.0(1H, d, J                   = 2.1Hz); 8.1(1H, d, J = 8.7Hz); 10.5(1H, s, ex-                   changeable with CF.sub.3 COOD)                              m.p. 94-96° C. NMR (DMSO-d.sub.6):                              1.25(6H, s); 13.0(6H, s); 1.4(1H, s); 6.45(2H,                              s, exchange- able with CF.sub.3 COOD); 7.65(1H,                              dd, J = 8.7 Hz and 2Hz); 7.95(1H, d, J =                              8.7Hz); 8.05(1H, d, J = 2Hz); 10.2(1H, s,                              exchange- able with CF.sub.3 COOD)    20   H.sub.3 C--(CH.sub.2).sub.4 --                   m.p. 60-63° C.                              m.p. 80-83° C.                   NMR (DMSO-d.sub.6):                              NMR (DMSO-d.sub.6):                   0.95(3H, t,                              0.90(3H, t,                   J = 6.8Hz);                              J = 6.8Hz);                   1.35(4H, m);                              1.35(4H, m);                   1.7(2H, m);                              1.65(2H, m);                   2.4(2H, t, 2.4(2H, t,                   J = 7.35Hz);                              J = 7.3Hz);                   7.35(3H, m);                              6.45(2H, s, exchange-                   7.55(2H, m);                              able with CF.sub.3 COOD);                   7.7(1H, dd,                              7.7(1H, dd,)                   J = 8.7Hz and                              J = 8.7Hz and                   2Hz); 8.1(1H, d,                              1.8Hz); 7.95(1H, d,                   J = 2Hz);  J = 8.7Hz);                   8.2(1H, d, 8.0(1H, d,                   J = 8.7Hz);                              J = 1.8Hz);                   10.4(1H, s, ex-                              10.5(1H, s, exchange-                   changeable with                              able with CF.sub.3 COOD)                   CF.sub.3 COOD)    21         5 #STR29##                   NMR (DMSO-d.sub.6): 1.1(2H, m); 1.45-1.7(6H, m); 2.15(1H,                   m); 2.3(2H, d), J = 7.3Hz); 7.25(3H, m); 7.4(2H, m);                   7.6(1H, dd, J = 8.7Hz and 2.0Hz); 8.0(1H, d, J = 2.0Hz);                   8.05(1H, d, (J = 8.7Hz); 10.3(1H, s, ex- changeable with                   CF.sub.3 COOD)                              m.p. 113-115° C. NMR (DMSO-d.sub.6):                              0.95(2H, m); 1.3(4H, m); 1.5(2H, m); 2.0(1H,                              m); 2.1(2H, d, J = 7.35Hz); 6.15(2H, s,                              exchange- able with CF.sub.3 COOD); 7.4(1H, dd,                              J = 8.7Hz and 2Hz); 7.7(2H, m); 10.2(1H, s,                              exchange- able with CF.sub.3 COOD)    22         6 #STR30##                   NMR (DMSO-d.sub.6): 2.7(2H, t, J = 7.7Hz); 2.95(2H, t, J =                   7.7Hz); 7.3(8H, m); 7.5(2H, m); 7.65(1H, dd, J = 8.7Hz and                   2Hz); 8.0(1H, d, J = 2Hz); 8.1(1H, d, J = 8.7Hz); 10.5(1H,                   s, ex- changeable with CF.sub.3 COOD)                              m.p. 122-123° C. NMR (DMSO-d.sub.6):                              2.7(2H, t, J = 7.7Hz); 2.9(2H, t, J = 7.7Hz);                              6.4(2H, s, exchange- able with CF.sub.3 COOD);                              7.25(5H, m); 7.6(1H, dd, J = 8.7Hz and 2Hz);                              7.9(2H, m); 10.5(1H, s, exchange- able with                              CF.sub.3 COOD)    23         7 #STR31##                   NMR (DMSO-d.sub.6): 1.45(3H, d, J = 7Hz); 3.9(1H, q,  J =                   7Hz); 7.3-7.5)(10H, m); 7.7(1H, dd, J = 8.7Hz and 2Hz);                   8.0(1H, d, J = 2Hz); 8.1(1H, d, J = 8.7Hz); 10.55(1H, s,                   ex- changeable with CF.sub.3 COOD)                              m.p. 136-137° C. NMR (DMSO-d.sub.6):                              1.4(3H, d, J = 7Hz); 3.85(1H, q, J = 7Hz);                              6.4(2H, s, exchangeable with  CF.sub.3 COOD);                              7.3(5H, m); 7.6(1H, dd, J = 8.7Hz and 2Hz);                              7.9(2H, m); 10.6(1H, s, exchange- able with                              CF.sub.3 COOD)    24         8 #STR32##                   m.p. 121-124° C.  NMR (DMSO-d.sub.6): 3.8(2H, s);                   7.4(8H, m); 7.5(2H, m); 7.75(1H, dd, J = 8.7Hz and                   2.05Hz); 8.1(1H, d, J = 2.05Hz); 8.2(1H, d, J = 8.7Hz);                   10.8(1H, s, ex- changeable with CF.sub.3 COOD)                              m.p. 105-107° C. NMR (DMSO-d.sub.6):                              3.85(2H, s); 6.5(2H, s, exchange- able with                              CF.sub.3 COOD); 7.4-7.5(5H, m); 7.8(1H, dd, J =                              8.7Hz and 2Hz); 8.1(2H, m); 10.9(1H, s,                              exchange- able with CF.sub.3 COOD)    25         9 #STR33##                   m.p. 176° C. NMR (DMSO-d.sub.6): 7.4(3H, m);                   7.6(4H, m); 8.0(1H, dd, J = 8.7Hz and 2Hz); 8.15(2H, m);                   8.25(2H, m); 8.5 (1H, s); 11.0(1H, s, exchangeable with                   CF.sub.3 COOD)                              m.p. 210-211° C. NMR (DMSO-d.sub.6):                              6.43(2H, s, exchange- able with CF.sub.3 COOD);                              7.5(2H, m); 7.9-8.2 (5H, m); 8.45(1H, s);                              11.0(1H, s, exchange- able with CF.sub.3 COOD)    26         0 #STR34##                   m.p. 186-188° C. NMR (DMSO-d.sub.6): 7.35-7.60(7H,                   m); 7.8(1H, d, J = 8.4Hz); 7.95(2H, m); 8.1(1H, dd, J =                   8.7Hz and 2Hz); 8.25(2H, m); 11.05(1H, s, ex- changeable                   with  CF.sub.3 COOD)                              m.p. (199-200° C. NMR(DMSO-d.sub.6):                              6.45(2H, s, exchange- able with CF.sub.3 COOD);                              7.4(1H, m); 7.55 (1H, m); 7.85(1H, m); 7.9(2H,                              m); 7.95(2H, m); 8.2(1H, s); 11.0 (1H, s,                              exchangeable with CF.sub. COOD)    27         1 #STR35##                   m.p. 162-164° C. NMR (DMSO-d.sub.6): 4.8(2H, s);                   7.05(2H, m); 7.25-7.6(7H, m); 7.8(1H, m); 8.1(1H, d, J =                   2Hz); 8.15(1H, d, J = 8.7Hz); 10.65(1H, s, ex- changeable                   with CF.sub.3 COOD)                              m.p. 190-192° C. NMR (DMSO-d.sub.6):                              4.8(2H, s); 6.4(2H, s, exchange- able with                              CF.sub.3 COOD); 7.0(2H, m); 7.4 (2H, m);                              7.7(1H, dd, J = 8.75 and 2Hz); 7.9(2H, m);                              10.6(1H, s, exchange- able with CF.sub.3    __________________________________________________________________________                              COOD)

EXAMPLE 28 2-Chloro-N-3-chloro-4-nitromethylcarbonylphenyl!phenylacetamide

a) Phenyl 2-chloro-4- (2-chlorobenzyl)carbonylamino!benzoate

1.54 g (8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride are added to a suspension composed of 2 g (8 mmol) of thecompound prepared in Example 12a, of 1.28 g (10.4 mmol) of4-dimethylaminopyridine, and 80 ml of dichloromethane. The solutionobtained is stirred for 15 min at room temperature, before adding 1.45 g(8.4 mmol) of 2-chlorophenylacetic acid in 20 ml of dichloromethane. Thesolution is stirred for 18 hours at room temperature. 200 ml of waterand 20 ml of concentrated HCl are then added. The decanted organic phaseis washed with a 1N HCl solution, and then with a sodium hydroxidesolution, and with water until neutral, before being dried over Na₂ SO₄and concentrated. The residue is crystallized from 95° ethanol to give1.4 g of white powder (Yield=43%).

m.p.=160-163° C.; NMR (DMSO-d₆): 3.95 (2H,s); 7.3-7.4 (5H,m); 7.5(4H,m); 7.7 (1H,dd, J=8.7 Hz and 2.1 Hz); 8.05 (1H,d, J=2.1 Hz); 8.2(1H,d, J=8.7 Hz); 10.8 (1H,s, exchangeable with CF₃ COOD).

b) 2-Chloro-N- 3-chloro-4-nitromethylcarbonylphenyl!-phenylacetamide

This compound was obtained by carrying out the procedure as in Example1b.

m.p.=154-156° C.; NMR (DMSO-d₆): 3.95 (2H,s); 6.4 (2H,s exchangeablewith CF₃ COOD); 7.35 (2H,m); 7.45 (2H,m); 7.7 (1H,dd, J=8.7 Hz and 1.9Hz); 7.95 (2H,m); 10.8 (1H,s, exchangeable with CF₃ COOD).

EXAMPLES 29 AND 30

The compounds of Examples 29 and 30 were obtained by carrying out theprocedure starting with the amine prepared in Example 12a as in Example28. ##STR36## N-3-Chloro-4-nitromethylcarbonylphenyl!-1-(4-chlorophenyl)cyclopropylcarboxamide(Example 29)

N-3-Chloro-4-nitromethylcarbonylphenyl!-2-trifluoromethylphenylacetamide(Example 30)

    ______________________________________    Exam-                          Compounds    ples  R3--Z--(CR.sub.1 R.sub.2).sub.p                       Phenyl esters                                   --CO--CH.sub.2 NO.sub.3    ______________________________________    29          6 #STR37##   m.p. 119-121° C. NMR(DMSO-d.sub.6): 1.25(2H,                       m); 1.6(2H, m); 7.3-7.55(9H, m); 7.8(1H, dd, J=8.7Hz                       and 2Hz); 8.0(1H, d, J=2Hz); 8.15(1H, d, J=8.7Hz);                       9.7(1H, s, ex- changeable with CF.sub.3 COOD)                                   m.p. 159-160° C. NMR(DMSO-d.sub.6):                                   1.2(2H, m); 1.5(2H, m); - # 6.4(2H, s,                                   exchange- able with CF.sub.3 COOD);                                   7.4(4H, s); 7.7 (1H, m); 7.9(2H, m);                                   9.6(1H, s, exchange- able with CF.sub.3                                   COOD)    30          7 #STR38##   m.p. 160-162° C. NMR(DMSO-d.sub.6): 4.05(2H,                       s); 7.35(3H, m); 7.5-7.8(7H, m); 8.05(1H, d, J=2Hz);                       8.2(1H, d, J=8.7Hz); 10.8(1H, s, ex- changeable with                       CF.sub.3 COOD)                                   m.p. 160-162° C. NMR(DMSO-d.sub.6):                                   4.0(2H, s); 6.4(2H, s, exchange- able with                                   CF.sub.3 COOD);  - #7.5-7.75(5H, m);                                   7.9(2H, m); 10.7(1H, s, exchange- able                                   with CF.sub.3 COOD)    ______________________________________

EXAMPLE 31 N-3-Chloro-4-nitromethylcarbonylphenyl!-4-chlorobenzenesulfonamide

A mixture composed of 2 g (9.3 mmol) of the amine obtained in Example13, 1.5 ml (18.5 mmol) of pyridine, 2.95 g (13.9 mmol) of4-chlorobenzenesulfonic acid chloride and 80 ml of THF is heated for 16h at 40° C. After cooling, 100 ml of water and 5 ml of concentratedhydrochloric acid are added before extracting with ethyl acetate. Theorganic phase is washed with a dilute sodium hydroxide solution. Thisaqueous phase is then acidified with HCl and extracted with ethylacetate, which is then washed with water until neutral, dried over Na₂SO₄ and concentrated under vacuum. The residue is purified bychromatography on a silica column in a dichloromethane/methanol (98:2)mixture. NMR (DMSO-d₆): 6.25 (2H, s, exchangeable with CF₃ COOD);7.0-7.3 (3H,m); 7.6-7.9 (4H,m); 11.2 (1H, broad s, exchangeable with CF₃COOD).

EXAMPLE 32 N- 3-Chloro-4-nitromethylcarbonylphenyl!benzenesulfonamide

a) Phenyl-2-chloro-4- phenylsulfonylamino!benzoate

A mixture composed of 10 g (40.4 mmol) of the amine prepared in Example12a, 6.5 ml (80.4 mmol) of pyridine, 10.7 g (60.5 mmol) ofbenzenesulfonic acid chloride and 200 ml of THF is stirred for 2 hoursat room temperature, before being heated at 40° C. for 14 hours. Aftercooling, 200 ml of water and 5 ml of concentrated HCl are added. Thereaction medium is extracted with dichloromethane, which is then washedwith water until neutral, dried over Na₂ SO₄ and concentrated undervacuum. The residue, purified by chromatography on a silica column withdichloromethane, gives 14.5 g of a light orange powder (Yield=92%).

m.p.=130-140° C.; NMR (DMSO-d₆): 7.2-7.4 (5H,m); 7.5 (2H,m); 7.65(3H,m); 7.8 (2H,dd, J=7.5 Hz and 0.8 Hz); 8.1 (1H,d, J=7.5 Hz); 11.25(1H,s, exchangeable with CF₃ COOD).

b) N- 3-Chloro-4-nitromethylcarbonylphenyl!benzenesulfonamide

The compound was obtained by carrying out the procedure as in Example1b.

NMR (DMSO-d₆): 6.4 (2H,s, exchangeable with CF₃ COOD): 7.25 (2H,m); 7.7(3H,m); 7.9 (3H,m); 11.2 (1H, broad s, exchangeable with CF₃ COOD)

EXAMPLE 33 Nitromethyl 2-chloro-4- N,N-di(phenylmethyl)amino!phenylketone

a) Phenyl 2-chloro-4- N,N-di(phenylmethyl)amino!benzoate

A mixture of 2.5 g (10 mmol) of the amine prepared in Example 12a, 2.7 g(20 mmol) of potassium carbonate, 6.8 g (40 mmol) of benzyl bromide, afew crystals of potassium iodide and 100 ml of dimethylformamide isheated at 80° C. for 6 hours. After cooling, the reaction medium ispoured into 300 ml of water, extracted with ethyl acetate, which is thenwashed with water, dried over Na₂ SO₄ and concentrated. The residual oilis triturated in hexane and the solid obtained is recrystallized fromethanol, to give 1.6 g of an off-white solid (Yield=37%).

m.p.=133-135° C.; NMR (DMSO-d₆): 4.8 (4H,s); 6.7-6.85 (2H,m); 7.1-7.5(15H,m); 7.9 (1H,m)

b) Nitromethyl 2-chloro-4- N,N-di(phenylmethyl)-amino!phenyl ketone

This compound was obtained by carrying out the procedure as in Example1b (Yield=40%).

m.p. 116-118° C.; NMR (DMSO-d₆): 4.9 (4H,s); 6.25 (2H, s, exchangeablewith CF₃ COOD); 6.8-6.9 (2H,m); 7.2-7.5 (10H,m); 7.7 (1H,d, J=9 Hz)

EXAMPLE 34 N- 2-Chloro-3-nitromethylcarbonylphenyl!acetamide

a) Phenyl 3-amino-2-chlorobenzoate

This compound was obtained from phenyl 2-chloro-3-nitrobenzoate bycarrying out the procedure as in Example 12a (Yield=97%).

m.p.=46-48° C.; NMR (DMSO-d₆): 5.5 (2H,s, exchangeable with CF₃ COOD);6.85 (1H,dd, J=7.45 Hz and 2.3 Hz); 7.0 (2H,m); 7.1 (3H,m); 7.3 (2H,m)

b) Phenyl 3-acetylamino-2-chlorobenzoate

This compound was obtained by carrying out the procedure as in Example12b (Yield=60%).

m.p.=120-122° C.; NMR (DMSO-d₆): 2.2 (3H, s); 7.4 (3H, m); 7.55 (3H, m);7.9 (1H, m); 8.0 (1H, m); 9.8 (1H, s, exchangeable with CF₃ COOD)

C) N- 2-Chloro-3-nitromethylcarbonylphenyl!acetamide

This compound was obtained by carrying out the procedure as in Example1b.

m.p.=140-142° C.; NMR (DMSO-d₆): 2.2 (3H, s); 6.5 (2H, s, exchangeablewith CF₃ COOD); 7.6 (1H, m); 7.8 (1H, dd, J=8 Hz and 1.3 Hz); 8.1 (1H,dd, J=8 Hz and 1.3 Hz); 9.8 (1H, s, exchangeable with CF₃ COOD)

EXAMPLE 35 N-2-Chloro-3-nitromethylcarbonylphenyl!-2-methylphenylacetamide

a) Phenyl 2-chloro-3- (2-methylbenzyl)carbonylamino!benzoate

This compound was obtained from phenyl 3-amino-2-chlorobenzoate and(2-methylphenyl)acetic acid chloride, the procedure being carried out asin Example 14a (Yield=78%).

m.p.=123-125° C.; NMR (CDCl₃): 2.3 (3H, s,); 3.75 (2H, s); 7.1-7.4 (10H,m); 7.65 (1H, m); 7.8 (1H, broad s, exchangeable with CF₃ COOD); 8.6(1H, dd, J=8.3 Hz and 1.55 Hz)

b) N- 2-Chloro-3-nitromethylcarbonylphenyl!-2-methylphenylacetamide

This compound was obtained by carrying out the procedure as in Example1b (Yield=45%).

m.p.=130-132° C.; NMR (DMSO-d₆): 2.25 (3H, s); 3.8 (2H, s); 6.4 (2H, s,exchangeable with CF₃ COOD); 7.1 (3H, m); 7.2 (1H, m); 7.45 (1H, m); 7.6(1H, dd, J=7.75 Hz and 1.4 Hz); 7.9 (1H, dd, J=8.1 Hz and 1.3 Hz); 9.8(1H, s, exchangeable with CF₃ COOD)

EXAMPLE 36 N- 4-Chloro-3-nitromethylcarbonylphenyl!acetamide

a) Phenyl 2-chloro-5-nitrobenzoate

This compound was obtained from 2-chloro-5-nitrobenzoic acid, theprocedure being carried out as in Example 1a (Yield=92%).

m.p.=83-85° C.; NMR (DMSO-d₆): 7.4 (3H, m); 7.55 (2H, m); 8.0 (1H, d,J=8.8 Hz); 8.5 (1H, dd, J=8.8 Hz and 2.7 Hz); 8.95 (1H, d, J=2.7 Hz)

b) Phenyl 5-amino-2-chlorobenzoate

18 g of Raney nickel are added to a solution of 59 g (212 mmol) of thecompound prepared in step a) in 600 ml of dioxane. The mixture ishyrogenated at a pressure of 70 kg at 65° C. After filtration of thecatalyst and concentration of the solvent, the residue is purified bychromatography on a silica column in dichloromethane and then in adichloromethane/hexane (1:1) mixture to give 29.3 g of a yellow solid(Yield=55%).

m.p.=84-86° C.; NMR (CDCl₃): 3.8 (2H, broad s, exchangeable with CF₃COOD); 6.7 (1H, m); 7.2 (5H, m); 7.35 (2H, m)

c) Phenyl 5-acetylamino-2-chlorobenzoate

This compound was obtained from the amine prepared in step b), theprocedure being carried out as in Example 12b (Yield=69%).

m.p.=141-143° C.; NMR (DMSO-d₆): 1.95 (3H, s); 7.2 (3H, m); 7.35 (2H, m)7.5 (1H, d, J=8.7 Hz); 7.75 (1H, dd, J=8.7 Hz and 2.6 Hz); 8.25 (1H, d,J=2.6 Hz); 10.25 (1H, s, exchangeable with CF₃ COOD)

d) N- 4-Chloro-3-nitromethylcarbonylphenyl!acetamide

The compound was obtained by carrying out the procedure as in Example 1b(Yield=15%).

m.p.=122-124° C.; NMR (DMSO-d₆): 2.2 (3H, s); 6.45 (2H, s exchangeablewith CF₃ COOD); 7.7 (1H, d, J=8.7 Hz); 7.9 (1H, dd, J=8.7 Hz and 2.5Hz); 8.2 (1H, d, J=2.5 Hz); 10.5 (1H, s, exchangeable with CF₃ COOD)

EXAMPLE 37 N-4-Chloro-3-nitromethylcarbonylphenyl!-2-methylphenylacetamide

a) Phenyl 2-chloro-5- (2-methylbenzyl)carbonylamino!-benzoate

This compound was obtained from the amine prepared in Example 36b, and(2-methylphenyl)acetic acid chloride, the procedure being carried out asin Example 14a (Yield=94%).

m.p.=102-104° C.; NMR (CDCl₃): 2.25 (3H, s); 3.75 (2H, s); 7.1-7.25 (9H,m, of which 1H is exchangeable with CF₃ COOD); 7.35 (3H, m); 7.7 (1H,dd, J=8.7 Hz and 2.2 Hz); 7.85 (1H, d, J=2.2 Hz).

b) N- 4-Chloro-3-nitromethylcarbonylphenyl!-2-methylphenylacetamide

This compound was obtained by carrying out the procedure as in Example1b (Yield=38%)

m.p.=148-150° C.; NMR (DMSO-d₆) 2.3 (3H, s); 3.8 (2H, s); 6.4 (2H, s,exchangeable with CF₃ COOD); 7.2 (4H, m); 7.6 (1H, d, J=8.7 Hz); 7.8(1H, dd, J=8.7 Hz and 2.5 Hz); 8.2 (1H, d, J=2.5 Hz); 10.6 (1H, s,exchangeable with CF₃ COOD)

EXAMPLE 38 N- 4-Chloro-3-nitromethylcarbonylphenyl!benzenesulfonamide

a) Phenyl 5- benzenesulfonylamino!-2-chlorobenzoate

This compound was obtained from the amine prepared in Example 36b bycarrying out the procedure as in Example 32a (Yield=97%).

m.p.=about 50° C.; NMR (DMSO-d₆): 7.3-7.7 (10H, m); 7.8 (3H, m); 10.8(1H, s, exchangeable with CF₃ COOD)

b) N- 4-Chloro-3-nitromethylcarbonylphenyl!benzenesulfonamide

This compound was obtained by carrying out the procedure as in Example1b.

m.p.=152-154° C.; NMR (DMSO-d₆): 6.2 (2H, s, exchangeable with CF₃COOD); 7.2 (1H, m); 7.35-7.65 (5H, m); 7.75 (2H, m); 10.8 (1H, s,exchangeable with CF₃ COOD)

EXAMPLE 39 2-(3-Chloro-4-nitromethylcarbonylphenyl)aminocarbonylmethylaminocarbonyl!benzoicacid

a) Phenyl2-chloro-4-((1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methylcarbonylamino)benzoate

This compound was obtained from the amine prepared in Example 12a, and(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)acetic acid chloride (preparedfrom the corresponding acid and SOCl₂, m.p.=80-83° C.), the procedurebeing carried out as in Example 14a (Yield=54%).

m.p.=220-222° C.; NMR (DMSO-₆): 4.55 (2H, s); 7.25 (3H, m); 7.4 (2H, m);7.6 (1H, m); 7.8-8.0 (5H, m); 8.1 (1H, d, J=8.6 Hz); 10.9 (1H, s,exchangeable with CF₃ COOD)

b) 2-(3-Chloro-4-nitromethylcarbonylphenyl)aminocarbonylmethylaminocarbonyl!benzoicacid

1.49 ml of nitromethane are added to a solution composed of 2.9 g (25.5mmol) of potassium tert-butoxide and 50 ml of DMSO, maintained at atemperature below 20° C. The mixture is stirred for one hour at atemperature below 20° C. before adding, dropwise, 3.7 g (8.5 mmol) ofthe phenyl ester prepared in step a) dissolved in 90 ml of DMSO. Afterstirring for 16 hours at room temperature, the reaction medium is pouredinto 750 ml of water. This aqueous phase is washed with ethyl acetateand acidified with HCL. The precipitate formed is filtered, washed withwater and dried under vacuum before being recrystallized fromacetonitrile to give 2.2 g of a white powder (Yield=61%).

m.p.=206-209° C.; NMR (DMSO-d₆): 4.0 (2H, d, J=5.6 Hz, is converted tosinglet with CF₃ COOD); 6.3 (2H,s, exchangeable with CF₃ COOD); 7.4-8.0(7H, m); 8.75 (1H, t, J=s.6 Hz, exchangeable with CF₃ COOD); 10.3 (1H,s, exchangeable with CF₃ COOD); 13.1 (exchangeable with CF₃ COOD)

EXAMPLE 40 N-3-Chloro-4-nitromethylcarbonylphenyl!-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)acetamide

HCl gas is bubbled for 1.5 hours through a suspension composed of 2 g(4.8 mmol) of the compound prepared in Example 39b and 30 ml ofmethanol. The heating of the solution allows the dissolution of thesolid at around 60° C. After cooling, the precipitate formed is filteredand recrystallized from acetonitrile to give 0.4 g of an off-whitepowder (Yield=19%).

m.p.=121° C. (decomposition); NMR (DMSO-d₆): 4.5 (2H, s); 6.3 (2H, s,exchangeable with CF₃ COOD); 7.55 (1H, dd, J=8.7 Hz and 2 Hz); 7.8-8.0(6H, m); 10.9 (1H, s, exchangeable with CF₃ COOD).

EXAMPLE 41 1- 3-Chloro-4-nitromethylcarbonylphenyl!-3-(phenylsulfonyl)urea

a) Phenyl 2-chloro-4- phenylsulfonylaminocarbonylamino!benzoate

1.5 g (8.2 mmol) of phenylsulfonyl isocyanate in 20 ml ofdichloromethane are added, dropwise, to a suspension of 2.08 g (8.4mmol) of the amine prepared in Example 12a in 40 ml of dichloromethane.Complete solubilization is obtained upon addition of the first drops,followed by the formation of a thick precipitate. After stirring for 16hours at room temperature, the precipitate is filtered and washed withdichloromethane and dried at 80° C. under vacuum to give 2.2 g of awhite powder (Yield=62%).

m.p.=183-185° C.; NMR (DMSO-d₆): 7.0-7.9 (13H, m); 9.3 (1H, s,exchangeable with CF₃ COOD); 11.0 (1H, s, exchangeable with CF₃ COOD)

b) 1- 3-Chloro-4-nitromethylcarbonylphenyl!-3-(phenylsulfonyl)urea

This compound was obtained by carrying out the procedure as in Example1b (Yield=49%).

m.p.=168-169° C.; NMR (DMSO-d₆): 6.35 (2H, s, exchangeable with CF₃COOD); 7.35 (1H, m); 7.5-7.7 (4H, m); 7.8 (1H, d, J=8.7 Hz); 8.0 (2H,m); 9.5 (1H, s, exchangeable with CF₃ COOD); 11.3 (1H, broad s,exchangeable with CF₃ COOD).

EXAMPLE 42 Nitromethyl 3-methyl-2-thienyl ketone

A solution composed of 10 g (70 mmol) of 3-methyl-2-thiophenecarboxylicacid, 3.4 g (56 mmol) of nitromethane and 115 ml of DMF is cooled to 0°C. 11.9 g (72.8 mmol) of diethyl cyanophosphonate in 56 ml of DMF, andthen 18.2 g (180 mmol) of triethylamine in 56 ml of DMF are addedthereto successively. The medium is then stirred for 2 hours at 0° C.and for 21 hours at room temperature. The reaction medium is poured over1 litre of a toluene/ethyl acetate (1:1) mixture, and extracted withwater. This aqueous phase, acidified with 40 ml of acetic acid, isextracted with a toluene/ethyl acetate (1:1) mixture. The organicextracts are washed with water and then with a saturated NaCl solutionin water, before being dried over Na₂ SO₄ and concentrated. The residue,purified by chromatography on a silica column in dichloromethane andthen by recrystallization from an ethyl acetate-hexane mixture, gives 2g of a pale yellow solid (Yield=19%).

m.p.=59-61° C.; NMR (CDCl₃): 2.6 (3H, s); 5.7 (2H, s, exchangeable withCF₃ COOD); 7.1 (1H, d, J=4.9 Hz); 7.6 (1H, d, J=4.9 Hz).

EXAMPLE 43 N-3-Chloro-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

a) 2-Chloro-4- (2-methylbenzyl)carbonylamino!benzoic acid

19.56 g (116 mmol) of (2-methylphneyl)acetic acid chloride are added,over 1 hour, to a mixture of 20 g (116 mmol) of 4-amino-2-chlorobenzoicacid, 12.9 g (127 mmol) of triethylamine and 150 ml of DMF dried over amolecular sieve. After stirring for 16 h at room temperature, the DMF isremoved by evaporation under vacuum. The residue is washed with waterand with dichloromethane to give, after drying, 19 g of an off-whitepowder (Yield=53%).

m.p.=214-218° C.; NMR (DMSO-d₆): 2.25 (3H, s); 3.8 (2H, s); 7.1-7.25(4H, m); 7.55 (1H, dd, J=8.6 Hz and 2 Hz); 7.8 (1H, d, J=8.6 Hz); 7.9(1H, d, J=2 Hz); 10.6 (1H, s, exchangeable with CF₃ COOD); 13.1 (1H,broad s, exchangeable with CF₃ COOD).

b) N- 3-Chloro-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

This compound was obtained by carrying out the procedure as in Example42 starting with 19 g (62.5 mmol) of 2-chloro-4-(2-methylbenzyl)carbonylamino!benzoic acid obtained in step a), 3.18 gof nitromethane, 11 g (67.6 mmol) of diethyl cyanophosphonate, 16.8 g(167 mmol) of triethylamine in 205 ml of DMF dried over a molecularsieve. After chromatography on a silica column (eluent:dichloromethanemethanol 95:5) and recrystallization from a hexane-ethylacetate mixture, 0.2 g (Yield=1%) of a pale yellow powder is obtained.

m.p.=133-135° C.; NMR (DMSO-d₆): 2.3 (3H, s); 3.8 (2H, s); 6.45 (2H, s,exchangeable with CF₃ COOD); 7.2-7.3 (4H, m); 7.75 (1H, dd, J=8.7 Hz and2 Hz); 7.9 (2H, m); 10.8 (1H, s, exchangeable with CF₃ COOD).

Removal of the washings makes it possible to isolate 5.2 g (Overallyield=30%) of a product identical to the first batch.

This compound is also obtained from the amine prepared in Example 12a bycarrying out the procedure as in Example 28.

The phenyl ester intermediate (m.p.=120-123° C., yield=56%) is convertedto the compound --CO--CH₂ --NO₂ (m.p.=141-143° C. (acetonitrile)) with ayield of 43%.

EXAMPLE 44 N- 3-Chloro-4-nitromethylcarbonylphenyl!-2-oxopiperidine

a) Phenyl 2-chloro-4- 5-chloropentanoylamino!benzoate

This compound was obtained by carrying out the procedure as in Example14a, starting with the compound prepared in Example 12a and5-chloropentanoic acid chloride.

NMR (DMSO-d₆): 1.8 (4H, m); 2.5 (2H, t, J=6.7 Hz); 3.75 (2H, t, J=6.7Hz); 7.3-7.6 (5H, m); 7.7 (1H, dd, J=8.7 Hz and 2 Hz); 8.1 (1H, d, J=2Hz); 8.2 (1H, d, J=8.7 Hz); 10.5 (1H, s, exchangeable with CF₃ COOD).

b) N- 3-Chloro-4-nitromethylcarbonylphenyl!-2-oxopiperidine

This compound was obtained by carrying out the procedure as in Example1b (Yield=67%).

m.p.=119-120° C.; NMR (DMSO-d₆): 1.85 (4H, m); 2.45 (2H, t, J=6.3 Hz);3.7 (2H, t, J=5.5 Hz); 6.4 (2H, s, exchangeable with CF₃ COOD); 7.5 (1H,dd, J=8.5 Hz and 2 Hz); 7.7 (1H, d, J=2 Hz); 7.9 (1H, d, J=8.5 Hz)

EXAMPLES 45 and 46

The following are obtained starting with the amine prepared in Example12a, the procedure being carried out as in Example 14:

N-3-Chloro-4-nitromethylcarbonylphenyl!-1-(4-chlorophenyl)cyclopentanecarboxamide(Example 45)

N-3-Chloro-4-nitromethylcarbonylphenyl!-2,3-dihydro-1H-indene-2-acetamide(Example 46)

    ______________________________________    Exam-                          Compounds    ples  R.sub.3 --Z--(CR.sub.1 R.sub.2).sub.p                       Phenyl esters                                   --CO--CH.sub.2 NO.sub.2    ______________________________________    45          8 #STR39##   m.p. 118-120° C. NMR(DMSO-d.sub.6): 1.7(4H, m);                       2.0 (2H, m); 2.7 (2H, m); 7.3(3H, m); 7.5(6H, m);                       7.8(1H, dd, J=9Hz and 2Hz); 8(1H, d, J=2Hz); 8.15(1H,                       d, J=9Hz); 9.7 (1H, s, ex- changeable with CF.sub.3                       COOD)       m.p=pasty solid NMR(DMSO-d.sub.6): 1.6                                   (4H, m); 1.9(2H, m); - # 2.6(4H, m); 6.4                                   (2H, s, exchangeable with CF.sub.3 COOD);                                   7.4 (4H, s); 7.75(1H, dd, J=9Hz and 2Hz);                                   7.9(1H, d, J=9Hz); 7.95(1H, d, J=2Hz);                                   9.7(1H, s, exchange- ble with CF.sub.3                                   COOD)    46          9 #STR40##   NMR(DMSO-d.sub.6): 2.5(4H, m); 2.8 (1H, m); 3.1(2H,                       m); 7.6(1H, dd, J=9Hz and 2Hz); 8(1H, d, J=2Hz);                       8.1(1H, d, J= 9Hz); 10.5(1H, s, exchangeable with                       CF.sub.3 COOD)                                   m.p. 157-157.5° C.                                   NMR(DMSO-d.sub.6): 2.5 (4H, m); 2.8(1H,                                   m); 3.1(2H, m); 6.3 (2H, s, exchangeable                                   with CF.sub.3 COOD); 7.1 - #(4H, m);                                   7.6(1H, dd; J=9Hz and 2Hz); 7.8 (1H, d,                                   J=9Hz); 7.9 (1H, d, J=2Hz); 10.4(1H, s,                                   exchange- able with CF.sub.3 COOD)    ______________________________________

EXAMPLES 47 to 57

The following are obtained starting with the amine prepared in Example12a, the procedure being carried out as in Example 28:

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-chlorobenzeneacetamide(Example 47)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-3-chlorobenzeneacetamide(Example 48)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-3,4-dichlorobenzeneacetamide(Example 49)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-methylbenzeneacetamide(Example 50)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-3-methylbenzeneacetamide(Example 51)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-3,4-dimethylbenzeneacetamide(Example 52)

N-3-Chloro-4-nitromethylcarbonylphenyl!-4-trifluoromethylbenzeneacetamide(Example 53)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-methoxybenzeneacetamide(Example 54)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-nitrobenzeneacetamide(Example 55)

4-Bromo-N-3-chloro-4-nitromethylcarbonylphenyl!-2-fluorobenzeneacetamide (Example56)

N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-fluorobenzeneacetamide(Example 57)

    __________________________________________________________________________                              Compounds    Examples         R.sub.3 --Z--(CR.sub.1 R.sub.2).sub.p                   Phenyl esters                              --CO--CH.sub.2 NO.sub.2    __________________________________________________________________________    47         2 #STR41##                   m.p. 140-142° C. NMR (DMSO-d.sub.6): 3.8 (2H, s);                   7.4(9H, m); 7.7(1H, dd, J = 9Hz and 2Hz); 8.0 (1H, d, J =                   2Hz); 8.2(1H, d, J = 9Hz); 10.8(1H, s, exchangeable with                   CF.sub.3 COOD)                              m.p. 158-160° C. NMR (DMSO-d.sub.6): 3.6                              (2H, s); 6.3(2H, s, exchangeable with CF.sub.3                              COOD); 7.4(4H, m); 7.6(1H, dd, J = 9Hz and                              2Hz); 7.9 (2H, m); 10.7(1H, s, exchangeable                              with CF.sub.3 COOD)    48         3 #STR42##                   m.p. 112-114° C. NMR (DMSO-d.sub.6): 3.8 (2H, s);                   7.4(9H, m); 7.75(1H, dd, J = 9Hz and 2Hz); 8.0 (1H, d, J =                   2Hz); 8.2(1H, d, J = 9Hz); 10.8(1H, s, exchangeable with                   CF.sub.3 COOD)                              m.p. 131-134° C. NMR (DMSO-d.sub.6): 3.7                              (2H, s); 6.35(2H, s, exchangeable with CF.sub.3                              COOD); 7.3(4H, m); 7.6(1H, dd, J = 9Hz and                              2Hz); 7.9 (2H, m); 10.7(1H, s, exchangeable                              with CF.sub.3 COOD)    49         2 #STR43##                   m.p. 155-158° C. NMR (DMSO-d.sub.6): 3.8 (2H, s);                   7.2-7.7 (9H, m); 8.0(1H, d, J = 2Hz); 8.2(1H, d, J = 9Hz);                   10.8 (1H, s, exchangeable with CF.sub.3 COOD)                              m.p. = 160-162° C. NMR (DMSO-d.sub.6):                              3.7 (2H, s); 6.4(2H, s, exchangeable with                              CF.sub.3 COOD); 7.3(1H, dd, J = 8Hz and 2Hz);                              7.6(3H. m); 7.9 (2H, m); 10.7(1H, s,                              exchangeable with CF.sub.3 COOD)    50         4 #STR44##                   m.p. = 130-132° C. NMR (DMSO-d.sub.6): 2.0 (3H, s);                   3.4(2H, s); 7.1(7H, m); 7.3 (2H, m); 7.4(1H, dd, J = 9Hz                   and 2Hz); 7.8(1H, d, J = 2Hz); 7.95(1H, d, J = 9Hz);                   10.4(1H, s, exchangeable with CF.sub.3 COOD)                              m.p. = 132-133° C. NMR (DMSO-d.sub.6):                              2.3 (3H, s); 3.6(2H, s); 6.3(2H, s, exchange-                              able with CF.sub.3 COOD); 7.15(4H, m); 7.6 (1H,                              dd, J = 9Hz); 7.9(2H, m); 10.6 (1H, s,                              exchangeable with CF.sub.3 COOD)    51         5 #STR45##                   m.p. =  126-128° C. NMR (DMSO-d.sub.6): 2.3 (3H,                   s); 3.7(2H, s); 7.2(7H, m); 7.5 (2H, m); 7.7(1H, dd, J =                   9Hz and 2Hz); 8.1(1H, d, J = 2Hz); 8.2(1H, d, J = 9Hz);                   10.8(1H, s, exchangeable with CF.sub.3 COOD)                              m.p. = 115-117° C. NMR (DMSO-d.sub.6):                              2.2 (3H, s); 3.5(2H, s); 6.3(2H, s, exchange-                              able with CF.sub.3 COOD); 7.0(4H, m); 7.55 (1H,                              dd, J = 7.6Hz and 1.7Hz); 7.8 (2H, m); 10.7(1H,                              s, exchangeable with CF.sub.3 COOD)    52         6 #STR46##                   m.p. = 156-158° C. NMR (DMSO-d.sub.6): 2.2 (6H,                   2s); 3.7 (2H, s); 7.1(3H, m); 7.3(3H, m); 7.5 (2H, m);                   7.7(1H, dd, J = 9Hz and 2Hz); 8(1H, d, J = 2Hz); 8.15(1H,                   d, J = 9Hz); 10.8(1H, s, exchangeable with CF.sub.3                              m.p. = 128-129° C. NMR (DMSO-d.sub.6):                              2.1 (6H, 2s); 3.5(2H, s); 6.25(2H, s,                              exchangeable with CF.sub.3 COOD); 7.0(3H, m);                              7.5 (1H, dd, J = 9Hz and 2Hz); 7.85(2H, m);                              10.7(1H, s, exchange- able with CF.sub.3 COOD)    53         7 #STR47##                   m.p. = 135-137° C. NMR (DMSO-d.sub.6): 3.9 (2H, s);                   7.3-7.8 (10H, m); 8.0 (1H, d, J = 2Hz); 8.15(1H, d, J =                   9Hz); 10.8(1H, s, exchangeable wit CF.sub.3 COOD)                              m.p. = 164-165° C. NMR (DMSO-d.sub.6):                              3.8 (2H, s); 6.4(2H, s, exchangeable with                              CF.sub.3 COOD); 7.6(5H, m); 7.9(2H, m); 10.8                              (1H, s, exchangeable with CF.sub.3 COOD)    54         8 #STR48##                   m.p. = 147-149° C. NMR (DMSO-d.sub.6): 3.6 (2H, s);                   3.8(3H, s); 6.9(2H, s); 7.3 (5H, m); 7.5(2H, m); 7.7(1H,                   dd, J = 8Hz and 2Hz); 8.0  (1H, d, J = 2Hz); 8.15(1H, d, J                   = 8Hz); 10.7(1H, s, exchangeable with CF.sub.3 COOD)                              m.p. 147-149° C. NMR (DMSO-d.sub.6):                              3.75 (2H, s); 3.8(3H, s); 6.5(2H, s, exchange-                              able with CF.sub.3 COOD); 7.0(2H, m); 7.4 (2H,                              m); 7.7(1H, dd, J = 9Hz and 2Hz); 8.1 (2H, m);                              10.8(1H, s, exchangeable with CF.sub.3 COOD)    55         1 #STR49##                   m.p. 180-182° C. NMR (DMSO-d.sub.6): 4.0 (2h, s);                   7.4(3H, m); 7.5(2H, m); 7.7 (3H, m); 8.0(1H, d, J =                   2Hz);8.15 (1H, J = 8.5Hz); 8.25(2H, m); 10.8 (1H, s,                   exchangeable with CF.sub.3 COOD)                              m.p. 192-193° C. NMR (DMSO-d.sub.6): 3.9                              (2H, s); 6.3(2H, s, exchangeable with CF.sub.3                              COOD); 7.6(3H, m); 7.8(2H, m); 8.2 (2H, m);                              10.8(1H, s, exchangeable with CF.sub.3 COOD)    56         9 #STR50##                   m.p. = 173-175° C. NMR (DMSO-d.sub.6): 3.9 (2H, s);                   7.5(8H, m); 7.7(1H, dd, J = 8.6hz and 1.9Hz); 8.1(1H, d, J                   = 1.9Hz); 8.2(1H, d, J = 8.6Hz); 10.8 (1H, s, exchangeable                   with CF.sub.3 COOD)                              m.p. 165-167° C. NMR (DMSO-d.sub.6): 3.8                              (2H, s); 6.25(2H, s, exchangeable with CF.sub.3                              COOD); 7.3(2H, m); 7.55(2H, m); 10.7(1H, s,                              exchangeable with CF.sub.3 COOD)    57         0 #STR51##                   m.p. 132-134° C. NMR (DMSO-d.sub.6): 3.75 (2H, s);                   7.4(9H, m);    7.7(1H, dd, J = 9Hz and 2Hz); 8.0 (1H, d, J                   = 2Hz); 8.15(1H, d, J = 9Hz); 10.7(1H, s, exchangeable                   with CF.sub.3 COOD)                              m.p. 139-141° C. NMR (DMSO-d.sub.6): 3.8                              (2H, s); 6.5(2H, s, exchangeable with CF.sub.3                              COOD): 7.3(2H, m); 7.5(2H, m); 7.75 (1H, dd, J                              = 9Hz and 2Hz); 8.0(2H, m); 10.8(1H, s,                              exchange- able with CF.sub.3 COOD)    __________________________________________________________________________

EXAMPLE 58 N- 3-Chloro-4-nitromethylcarbonylphenyl!-2-propeneamide

Obtained by carrying out the procedure as in Example 31, starting withthe amine prepared in Example 13, in the presence of triethylamine andin dichloromethane.

m.p. 140-144° C.; NMR (DMSO-d₆): 6.35 (2H, s, exchangeable with CF₃COOD); 6.8 (1H, d, J=12 Hz); 7.4 (3H, m); 7.65 (4H, m); 7.9 (1H, d, J=9Hz); 8.1 (1H, d, J=2 Hz); 10.8 (1H, s, exchangeable with CF₃ COOD).

EXAMPLE 59 N-3-Methyl-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

a) Phenyl 2-methyl-4-nitrobenzoate

Obtained by carrying out the procedure as in Example 1a, starting with2-methyl-4-nitrobenzoic acid.

b) Phenyl 4-amino-2-methylbenzoate

A mixture composed of 3.5 g (13.6 mmol) of the nitro derivative preparedin Example 59a, 1 g of Raney nickel and 35 ml of dioxane is subjected toa hydrogen pressure of about 100 atm, for 2.5 h at 80° C. After cooling,filtration of the reaction medium, and concentration, 2.7 g of a pastysolid are obtained.

NMR (DMSO-d₆): 2.5 (3H, s); 6.1 (2H, s, exchangeable with CF₃ COOD); 6.5(2H, m); 7.2 (3H, m); 7.4 (2H, m); 7.8 (1H, d, J=8.3 Hz)

c) Phenyl 2-methyl-N- (2-methylphenyl)carbonylamino!benzoate

Obtained by carrying out the procedure as in Example 14a, starting withthe amine prepared in Example 59b and (2-methyl)phenylacetic acidchloride (Yield=86%).

NMR (DMSO-d₆): 2.3 (3H, s); 2.6 (3H, s); 3.7 (2H, s); 7.1-7.7 (11H, m);8.1 (1H, d, J=9 Hz); 10.5 (1H, s, exchangeable with CF₃ COOD).

d) N- 3-Methyl-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

Obtained by carrying out the procedure as in Example 1b, starting withthe phenyl ester prepared in Example 59c.

m.p. 159-160° C.; NMR (DMSO-₆): 2.1 (3H, s); 2.25 (3H, s); 3.5 (2H, s);6.15 (2H, s, exchangeable with CF₃ COOD); 7.0 (4H, m); 7.3 (1H, d, J=1.6Hz); 7.45 (1H, dd, J=8.5 Hz and 1.6 Hz); 7.6 (1H, d, J=8.5 Hz); 10.4(1H, s, exchangeable with CF₃ COOD)

EXAMPLE 60 N-2-Bromo-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

a) 3-Bromo-4-( 2-methylphenyl)carbonylamino!benzoic acid

Obtained by carrying out the procedure as in Example 43a, starting with4-amino-3-bromobenzoic acid and 2-methylphenylacetic acid chloride(Yield=86%).

NMR (DMSO-d₆): 2.1 (3H, s); 3.6 (2H, s); 6.9 (3H, m) 7.0 (1H, m); 7.75(1H, m); 7.9 (1H, d, J=1.3 Hz); 9.3 (1H, s, exchangeable with CF₃ COOD);13.0 (1H, broad s, exchangeable with CF₃ COOD)

b) Phenyl 3-bromo-4- (2-methylphenyl)carbonylamino!benzoate

Obtained by carrying out the procedure as in Example 1a (Yield=98%)

m.p. 139-141° C.; NMR (DMSO-d₆): 2.4 (3H, s); 3.9 (2H, s); 7.2-7.5 (9H,m); 8.1 (2H, m); 8.3 (1H, d, J=1.8 Hz); 9.7 (1H, s, exchangeable withCF₃ COOD).

c) N- 2-Bromo-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

Obtained by carrying out the procedure as in Example 1b (Yield=41%)

m.p. 125-127° C.; NMR (DMSO-d₆): 2.2 (3H, s); 3.7 (2H, s); 6.3 (2H, s,exchangeable with CF₃ COOD); 7.1 (4H, m); 7.8 (1H, dd, J=9 Hz and 2 Hz);7.9 (1H, m); 8.1 (1H, d, J=2 Hz); 9.5 (1H, s, exchangeable with CF₃COOD).

EXAMPLE 61 Nitromethyl 2-chloro-4-methoxyphenyl ketone

a) Phenyl 2-chloro-4-methoxybenzoate

Obtained by carrying out the procedure as in Example 1a, starting with2-chloro-4-methoxybenzoic acid (Yield=770%)

NMR (CDCl₃): 3.8 (3H, s); 6.8 (1H, dd, J=9 Hz and 2.5 Hz); 6.95 (1H, d,J=2.5 Hz); 7.15 (3H, n); 7.3 (2H, m); 8.0 (1H, d, J=9 Hz)

b) Nitromethyl 2-chloro-4-methoxyphenyl ketone

Obtained by carrying out the procedure as in Example 1b.

NMR (DMSO-d₆): 3.9 (3H, s); 6.4 (2H, s, exchangeable with CF₃ COOD); 7.1(1H, dd, J=9 Hz and 2.5 Hz); 7.2 (1H, d, J=2.5 Hz); 7.9 (1H, d, J=9 Hz)

EXAMPLE 62 Nitromethyl 2-isopropylphenyl ketone

a) Phenyl 2-isopropylbenzoate

Obtained by carrying out the procedure as in Example 1a, starting with2-(1-methylethyl)benzoic acid (Yield=85%).

NMR (CDCl₃): 1.2 (6H, m); 3.8 (1H, m); 7.1-7.25 (4H, m); 7.3-7.5 (4H,m); 7.9 (1H, dd, J=8 Hz and 1.5 Hz)

b) Nitromethyl 2-isopropylphenyl ketone

Obtained by carrying out the procedure as in Example 1b

(Liquid)

NMR (CDCl₃): 1.5 (6H, m); 3.4 (1H, m); 5.7 (1H, s, exchangeable with CF₃COOD); 7.2-7.5 (4H, m)

EXAMPLE 63 N-4-Chloro-3-nitromethylcarbonylphenyl!-2-mnethylphenylacetamide

a) 5-Chloro-2- (2-methylphenyl) carbonylamino!benzoic acid

Obtained by carrying out the procedure as in Example 43a, starting with2-amino-5-chlorobenzoic acid and 2-methylphenylacetic acid chloride(Yield=75%)

m.p.=224-226° C. NMR (DMSO-d₆): 2.3 (3H, s); 3.8 (2H, s); 7.2 (4H, m);7.7 (1H, dd, J=9 Hz and 2.5 Hz); 7.9 (1H, d, J=2.5 Hz); 8.7 (1H, d, J=9Hz); 11.1 (1H, s, exchangeable with CF₃ COOD); 14.0 (1H, broad s,exchangeable with CF₃ COOD)

b) Phenyl 5-chloro-2- (2-methylphenyl)carbonylamino!benzoate

Obtained by carrying out the procedure as in Example 1a (Yield=38%)

c) N- 4-Chloro-2-nitromethylcarbonylphenyl-2-methylphenylacetamide

Obtained by carrying out the procedure as in Example 1b.

m.p.=128-130° C.; NMR (DMSO-d₆): 2.4 (3H, s); 3.9 (2H, s); 6.5 (2H, s,exchangeable with CF₃ COOD); 7.4 (4H, m); 7.9 (1H, dd, J=9 Hz and 2 Hz);8.1 (1H, d, J=2 Hz); 8.3 (1H, d, J=9 Hz); 10.9 (1H, s, exchangeable withCF₃ COOD)

EXAMPLE 64 Nitromethyl 2-chloro-4-phenylthiophenyl ketone

a) Phenyl 2-chloro-4-(phenylthio)benzoate

A solution of 4.15 g (60.5 mmol) of sodium nitrite in 20 ml of water isadded, at 0° C., to a suspension of 15 g (60.5 mmol) of the amineprepared in Example 12a, in 12.1 ml of 10N hydrochloric acid.

After stirring for one hour at 0° C., the medium is neutralized with asaturated sodium acetate solution. This mixture is poured, over 15minutes, over a solution, at 70-80° C., composed of 8 g (72.6 mmol) ofthiophenol, 3.85 g (96 mmol) of sodium hydroxide and 25 ml of water. Atthe end of the addition, the reaction medium is heated for 1 hour at 95°C. After cooling, the reaction medium is extracted with ethyl acetate.The organic phase, after washing with a dilute sodium hydroxide solutionand then with water, is dried over Na₂ SO₄ and concentrated undervacuum. The residue is purified by flash chromatography on silica(hexane) to give an orange-yellow liquid (Yield=31%).

NMR (DMSO-₆): 7.3-7.7 (12H, m); 8.1 (1H, m).

b) Nitromethyl 2-chloro-4-phenylthiophenyl ketone

Obtained by carrying out the procedure as in Example 1b.

m.p.=77-78° C.; NMR (DMSO-₆): 6.5 (2H, s); 7.3 (2H, m); 7.7 (5H, m);7.95 (1H, d, J=8.5 Hz)

EXAMPLE 65 N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-(3-chloro-4-nitromethylcarbonylphenyl)aminocarbonyl!-3-phenylbutanamide

a) Phenyl 2-chloro-4-3-chloro-4-(Phenoxycarbonyl)phenyl!amino!-1,5-dioxo-3-phenylpentyl!amino!benzoate

Obtained by carrying out the procedure as in Example 14, starting withthe amine prepared in Example 12a and a 1/2 equivalent of3-phenylglutaric acid dichloride.

NMR (DMSO-d₆): 2.8 (4H, m); 3.8 (1H, m); 7.1-7.6 (17H, m); 7.9 (2H, d,J=2 Hz); 8.1 (2H, d, J=9 Hz); 10.4 (2H, s, exchangeable with CF₃ COOD).

b) N- 3-Chloro-4-nitromethylcarbonylphenyl!-4-(3-chloro-4-nitromethylcarbonylphenyl)aminocarbonyl!-3-phenylbutanamide

Obtained by carrying out the procedure as in Example 1b.

m.p. 195-196° C.; NMR (DMSO-d₆): 2.8 (4H, m); 3.8 (1H, m); 6.4 (4H, s,exchangeable with CF₃ COOD); 7.3 (5H, m); 7.5 (2H, dd, J=9 Hz and 2 Hz);7.9 (4H, m); 10.5 (s, exchangeable with CF₃ COOD).

EXAMPLE 66 Nitromethyl 2-chloro-4-phenylsulfinylphenyl ketone

a) Phenyl 2-chloro-4-(phenylsulfinyl)benzoate

5 ml (40 mmol) of a 70% tert-butyl hydroperoxide solution in water areadded to a suspension of 2 g (5.9 mmol) of the compound prepared inExample 64a in 60 ml of water. The reaction medium is heated at 70° for32 h. After cooling, the peroxides are destroyed by addition of asolution of 10 g of sodium metabisulfite in 100 ml of water. Afterstirring for 2 hours and negative control for the peroxides, thereaction medium is extracted with dichloromethane. The organic phase iswashed with a saturated NaCl solution in water and dried over Na₂ SO₄.After concentration of the dichloromethane and purification by flashchromatography on a silica column (hexane-ethyl acetate 4:1), 0.1 g of acolourless oil is obtained (Yield=4%).

NMR (DMSO-d₆): 7.1 (3H, m); 7.2-7.4 (5H, m); 7.7 (3H, m); 7.8 (1H, d,J=1.6 Hz); 8.0 (1H, m)

b) Nitromethyl 2-chloro-4-phenylsulfinyl ketone

Obtained by carrying out the procedure as in Example 1b.

(Oil).

NMR (DMSO-d₆): 6.4 (2H, s, exchangeable with CF₃ COOD); 6.8 (3H, m); 7.2(2H, m); 7.6 (3H, m)

EXAMPLE 67 Nitromethyl 4-chloro-2-trifluoromethoxyphenyl) ketone

a) Phenyl 4-chloro-2-trifluoromethoxybenzoate

In a hermetically closed steel container, a mixture composed of 21.5 g(112 mmol) of 4-chloro-2-hydroxybenzoic acid chloride, 59.8 g (336 mmol)of antimony trifluoride, 3.2 g of antimony pentafluoride and 258 ml ofCCl₄, is heated at 175° C. for 6 h. After cooling, the reaction mediumis taken up in about 3 l of dichloromethane. The organic phase is washedwith water. The precipitate formed is washed with dichloromethane. Thecombined organic phases are dried over Na₂ SO₄ and concentrated to give19.2 g of a black liquid which is used without further purification.

The 19.2 g of the compound obtained above are mixed with 90 ml oftoluene, 75 ml of thionyl chloride and a few drops of DMF, are stirredfor 2 h at room temperature. The reaction medium is then concentratedunder vacuum. The residue obtained is diluted with 200 ml ofdichloromethane before being added to a mixture of 9.8 g of phenol, 16.2g of triethylamine and 100 ml of dichloromethane. After stirring for 16h at room temperature, the reaction medium is poured over an ice+HCLmixture. The mixture is extracted with dichloromethane, which is thenwashed with a dilute sodium hydroxide solution, and with water beforebeing dried over Na₂ SO₄, and concentrated. The residue is purified withchromatography on silica (hexane-ethyl acetate 4:1) to give 9.2 g of anorange-coloured liquid (Yield=37%).

b) Nitromethyl 4-chloro-2-trifluoromethoxyphenyl ketone

Obtained by carrying out the procedure as in Example 1b.

Pasty solid

NMR (CDCl₃): 5.7 (2H, s, exchangeable with CF₃ COOD); 7.3-7.5 (2H, m);8.0 (1H, d, J=9 Hz).

EXAMPLE 68 N-2-(3-Chloro-4-nitromethylcarbonylphenyl!-2-methylbenzenesulfonamide

a) Ethyl 2-chloro-4-(cyanomethyl)benzoate

3.1 g (11.2 mmol) of ethyl 4-(bromomethyl)-2-chlorobenzoate are addeddropwise to a solution composed of 0.94 g (14.3 mmol) of potassiumcyanide, 3.75 ml of water and 8.8 ml of ethanol, heated under reflux.After refluxing for 3 hours, the medium is poured over 200 ml of water,and extracted with ethyl acetate. The organic phase is washed with adilute HCl solution and then with water saturated with NaCl. The oilobtained after concentration of the organic phase is purified by flashchromatography on silica (hexane-ethyl acetate 1:0 to 1:1 gradient). 0.4g of a brown solid is obtained (Yield=16%).

m.p. 60° C.; NMR (CDCl₃): 1.4 (3H, t, J=7 Hz); 3.8 (2H, s); 4.5 (2H, q,J=7 Hz); 7.1 (1H, m); 7.5 (1H, d); 7.9 (1H, d)

b) Ethyl 4-(2-aminoethyl)-2-chlorobenzoate

A mixture composed of 1.9 g (8.5 mmol) of ethyl2-chloro-4-(cyanomethyl)benzoate, 0.5 g of Raney nickel in 70 ml ofmethanol containing a few ml of liquid ammonia is subjected to ahydrogen pressure of about 60 kg/cm², at 50° C. for 5 h, and then at 80°C. for 4.5 h. After filtration of the reaction medium, 1.5 g of oil areobtained (Yield=77%).

NMR (CDCl₃): 1.3 (3H, t, J=7 Hz); 1.7 (2H, broad s, exchangeable withCF₃ COOD); 2.6-3.0 (4H, m); 4.3 (2H, q, J=7 Hz); 7.0 (1H, m); 7.2 (1H,m); 7.6 (1H, d, J=6.3 Hz)

c) Ethyl 2-chloro-4- 2-(2-methylphenylsulfonylamino)ethyl!benzoate

Obtained by carrying out the procedure as in Example 32c (Yield=43%).

(Oil).

NMR (CDCL₃): 1.3 (3H, t, J=7 Hz); 2.4 (3H, s); 2.7 (2H, m); 3.1 (2H, m);4.3 (2H, q, J=7 Hz); 4.4 (1H, broad s, exchangeable with CF₃ COOD); 6.9(1H, m); 7.0 (1H, m); 7.1-7.4 (3H, m); 7.7 (1H, m); 7.8 (1H, dd, J=8 Hzand 1.25 Hz)

d) 2-Chloro-4- 2-(2-methylphenylsulfonylamino)ethylbenzoic acid

A mixture composed of 1 g (2.6 mmol) of the ethyl ester previouslyprepared, 18 ml of methanol, 18 ml of water and 0.2 g (5.2 mmol) of NaOHpellets, is heated for 4 h at 40° C. After concentration of the methanoland addition of 30 ml of water, the medium is washed with CH₂ Cl₂. Theaqueous phase is then acidified to give 0.675 g of a white precipitate(Yield=72%).

m.p. 122-124° C.; NMR (DMSO-₆): 2.3 (3H, s); 2.7 (2H, m); 3.0 (2H, m);7.0-7.8 (8H, m, of which 1H is exchangeable with CF₃ COOD); 13.1 (1H,broad s, exchangeable with CF₃ COOD)

e) Phenyl 2-chloro-4- 2-(2-methylphenylsulfonylamino)ethyl!benzoate

Obtained by carrying out the procedure as in 1a as the whole(Yield=61%).

(Oil).

NMR (CDCl₃): 2.4 (3H, s); 2.7 (2H, m); 3.2 (2H, m); 4.1 (1H, m,exchangeable with D₂ O); 7.0-8.0 (12H, m)

f) N-2-(3-Chloro-4-nitromethylcarbonylphenyl)ethyl!-2-methylbenzenesulfonamide

Obtained by carrying out the procedure as in Example 1b.

(Oil).

NMR (CDCl₃): 2.5 (3H, s); 2.7 (2H, t, J=5 Hz); 3.2 (2H, t, J=5 Hz); 4.4(1H, broad s, exchangeable with CF₃ COOD); 5.8 (2H, s, exchangeable withCF₃ COOD); 7.0-7.5 (5H, m); 7.6 (1H, m); 7.9 (1H, m)

EXAMPLE 69 N-3-Bromo-4-nitromethylcarbonylphenyl!-2-methylphenylacetamide

a) 2-Bromo-4- (2-methylbenzyl)carbonylamino!benzoic acid

Obtained by carrying out the procedure as in Example 43, starting with4-amino-2-bromobenzoic acid (Yield=23%).

m.p.=decomposition at 205° C.; NMR (DMCO-d₆): 2.4 (3H, s); 3.9 (2H, s);7.2 (4H, m); 7.6 (1H, dd, J=9 Hz and 2 Hz); 7.9 (1H, d, J=9 Hz); 8.2(1H, d, J=2 Hz); 10.7 (1H, s, exchangeable with CF₃ COOD); 13.0 (1H,broad s, exchangeable with CF₃ COOD)

b) Phenyl 2-bromo-4- (2-methylbenzyl)carbonylamino!benzoate

Obtain by carrying out the procedure as in Example 14a(Yield=quantitative)

(Oil).

NMR (DMSO-d₆): 2.0 (3H, s); 3.7 (2H, s); 6.8-7.3 (9H, m); 7.5 (1H, dd,J=8 Hz and 2 Hz); 7.8 (1H, d, J=8 Hz); 8.0 (1H, d, J=2 Hz); 10.5 (1H, s,exchangeable with CF₃ COOD)

c) Phenyl 2-bromo-4- (2-methylbenzyl)carbonylamino!benzoate

Obtained by carrying out the procedure as in Example 1b

(Oil).

NMR (DMSO-d₆): 2.4 (3H, s); 3.8 (2H, s); 6.5 (2H, s, exchangeable withCF₃ COOD); 7.2-7.6 (4H, m); 7.8 (1H, dd, J=9 Hz and 2 Hz); 8.0 (1H, d,J=9 Hz); 8.3 (1H, d, J=2 Hz); 10.9 (1H, s, exchangeable with CF₃ COOD)

EXAMPLE 70 N-3-Chloro-4-nitromethylcarbonylphenyl!-N-isopropylbenzenesulfonamide

a) Phenyl 2-chloro-4- (isopropyl)(phenylsulfonyl)amino!benzoate

10.1 g (25.5 mmol) of sodium hydride (at 55% in oil) are added to asolution of 9.9 g (25.5 mmol) of the compound prepared in Example 32a,in 100 ml of DMF. After stirring for 1 hour at room temperature, 9.4 g(76.5 mmol) of 2-bromopropane are added and the medium is stirred atroom temperature for 16 hours before heating at 60° C. for 34 hours. 5.1ml (51 mmol) of 2-iodopropane are then added. The reaction medium isthen heated for 4 hours at 60° C. before being poured over awater-ice-HCl mixture. The medium is extracted with ethyl acetate, whichis then dried and concentrated to give an oil. After purification bychromatography on a silica column (CH₂ Cl₂) 1.9 g of off-white crystalsare obtained (Yield=17%).

m.p. 120° C.; NMR (DMSO-d₆): 1.0 (6H, d, J=6.5 Hz); 4.4 (1H, m); 7.1-7.9(12H, m); 8.0 (1H, d, J=8 Hz)

b) N-3-Chloro-4-nitromethylcarbonylphenyl!-N-isopropylbenzenesulfonamide

Obtained by carrying out the procedure as in Example 1b, starting withthe phenyl ester prepared in Example 65a.

(Oil)

NMR (CDCl₃): 1.0 (6H, d, J=7 Hz); 4.5 (1H, q, J=7 Hz); 5.8 (2H, s,exchangeable with CF₃ COOD); 7.0 (1H, dd, J=9 Hz and 2 Hz); 7.15 (1H,m); 7.35-7.7 (6H, m).

What is claimed is:
 1. A compound of the formula: ##STR52## in which Arepresents C₆ -C₁₀ -aryl;X represents halogen, cyano, C₁ -C₇ -alkyl,trifluoromethyl, C₃ -C₇ alkoxy or trifluoromethoxy; R₁ and R₂, which areidentical or different, represent a hydrogen atom, a C₁ -C₇ -alkylgroup, a C₃ -Cl₁₂ -cycloalkyl group, a trifluoromethyl group, a C₁ -C₇-alkoxy group or R₁ and R₂ together form an alkylene chain --(CH₂)_(r)--, where r is chosen from 2, 3 and 4; p is chosen from 0, 1, 2, 3, 4and 5; Z represents a bond or a C₂ -C₇ -alkenylene radical; R₃represents a halogen atom; a C₁ -C₇ -alkyl group optionally substitutedwith one or more identical or different Y radicals; a C₆ -C₁₀ -arylgroup optionally substituted with one or more identical or different Yradicals; a C₆ -C₁₀ -aryloxy group optionally substituted with one ormore identical or different Y radicals; a C₃ -C₁₂ -cycloalkyl groupoptionally substituted with one or more identical or different Yradicals; Y represents a halogen atom, C₁ -C₇ -alkyl, C₁ -C₇ -alkoxy,trifluoromethyl, carboxy, carbamoyl, (C₁ -C₇)alkylcarbamoyl, di-(C₁-C₇)alkylcarbamoyl, C₁ -C₇ -alkoxycarbonyl, amino, C₁ -C₇ -alkylamino,di-(C₁ -C₇)-alkylamino, nitro, cyano, hydroxy, trifluoromethoxy, C₃ -C₁₂-cycloalkyl, sulfo, C₁ -C₇ -alkylthio, C₁ -C₇ -alkylsulfinyl, C₁ -C₇-alkylsulfonyl, C₂ -C₈ -alkylcarbonyl, C₂ -C₈ -alkylthiocarbonyl, C₂ -C₈-alkylcarbonylamino, or C₆ -C₁₀ -aryl; E represents a divalent radicalchosen from:(i) --CO--NR₄ -- in which the carbonyl group is linked to--(CR₁ R₂)_(p) -- and R₄ represents the radical --(CH₂)_(q) --R₅ where qis chosen from 0 and 1; and where R₅ represents a hydrogen atom; a C₁-C₇ -alkyl group, or a C₆ -C₁₀ -aryl group; or R₅ and R₃ together form abond; and (ii) --NR₄ -- in which R₄ is as defined above; n represents 0or 1;on the condition that --A(X)--(E)_(n) --(CR₁ R₂)_(p) --Z--R₃ doesnot represent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl,4-ethoxy-2-methylaminophenyl, 2-hydroxyphenyl substituted with a groupX, 2-methoxyphenyl substituted with a group X and optionally substituted2-fluorophenyl as defined above, and addition salts thereof withpharmaceutically acceptable bases.
 2. Compound according to claim 1, inwhich A represents phenyl and n and p represent 0 and Z represents abond.
 3. Compound according to claim 1, in which A represents phenyl, nis equal to 1 and E represents --CO--NR₄ --.
 4. Compound according toclaim 1, in which A represents phenyl, n and p are equal to 1, Erepresents --CO--NR₄ --, R₁ and R₂ represent a hydrogen atom and Zrepresents a bond.
 5. Compound according to claim 1, in which Arepresents naphthyl.
 6. Compound according to claim 1 chosen from:N-3-chloro-4-(nitromethylcarbonylphenyl)!-2-methylphenylacetamide, N-3-chloro-4-(nitromethylcarbonylphenyl)!-2-trifluoromethylphenylacetamideN- 3-chloro-4-(nitromethylcarbonylphenyl)!-phenylacetamide, N-3-chloro-4-(nitromethylcarbonylphenyl)!-2-chlorophenylacetamide, N-3-chloro-4-(nitromethylcarbonylphenyl)!-4-chlorobenzamide, nitromethyl2-trifluoromethoxyphenyl ketone, nitromethyl 2-methyl-1-naphthyl ketone,nitromethyl 3-chloro-2-naphthyl ketone, nitromethyl6-methoxy-5-trifluoromethyl-1-naphthyl ketone.
 7. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of at leastone compound of formula (I) according to claim 1, in combination with atleast one pharmaceutically acceptable vehicle.
 8. Composition accordingto claim 7, in the form of an immediate-release tablet, acontrolled-release tablet, a gelatin capsule, an injectable solution, acream or a collyrium.
 9. A composition according to claim 7 wherein thepharmaceutically acceptable amount of a compound of formula (I) is analdose reductase inhibiting amount.
 10. A process for the preparation ofa compound of formula (I) according to claim 1, comprising treating anacid of formula ##STR53## in which R₁, R₂, R₃, Z, E, n, p, A and X areas defined in claim 1, with a mixture of nitromethane and di(C₁-C₇)alkyl cyanophosphonate in the presence of a base.